Methods and compounds for inhibitting MRP1

ABSTRACT

The present invention further relates to a method of inhibiting MRP1 in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I).

BACKGROUND

[0001] Along with surgery and radiotherapy, chemotherapy continues to bean effective therapy for many cancers. In fact, several types of cancer,such as Hodgkin's disease, large cell lymphoma, acute lymphocyticleukemia, testicular cancer and early stage breast cancer, are nowconsidered to be curable by chemotherapy. Other cancers such as ovariancancer, small cell lung and advanced breast cancer, while not yetcurable, are exhibiting positive response to combination chemotherapy.

[0002] One of the most important unsolved problems in cancer treatmentis drug resistance. After selection for resistance to a single cytotoxicdrug, cells may become cross resistant to a whole range of drugs withdifferent structures and cellular targets, e.g., alkylating agents,antimetabolites, hormones, platinum-containing drugs, and naturalproducts. This phenomenon is known as multidrug resistance (MDR). Insome types of cells, this resistance is inherent, while in others, suchas small cell lung cancer, it is usually acquired.

[0003] Such resistance is known to be multifactorial and is conferred byat least two proteins: the 170 kDa P-glycoprotein (MDR1) and the morerecently identified 190 kDa multidrug resistance protein (MRP1).Although both MDR1 and MRP1 belong to the ATP-binding cassettesuperfamily of transport proteins, they are structurally very differentmolecules and share less than 15% amino acid homology. Despite thestructural divergence between the two proteins, by 1994 there were noknown consistent differences in the resistance patterns of MDR1 and MRP1cell lines. However, the association, or lack thereof, of MRP1 andresistance to particular oncolytics is known. See Cole, et. al.,“Pharmacological Characterization of Multidrug Resistant MP-transfectedHuman Tumor Cells”, Cancer Research, 54:5902-5910, 1994. Doxorubicin,daunorubicin, epirubicin, vincristine, paclitaxel, mitoxantrone,melphalan, and etoposide are substrates of MRP1, i.e., MRP1 can bind tothese oncolytics and redistribute them away from their site of action,the nucleus, and out of the cell. Id. and Marquardt, D., and Center, M.S., Cancer Research, 52:3157, 1992.

[0004] Doxorubicin, daunorubicin, and epirubicin are members of theanthracycline class of oncolytics. They are isolates of various strainsof Streptomyces and act by inhibiting nucleic acid synthesis. Theseagents are useful in treating neoplasms of the bone, ovaries, bladder,thyroid, and especially the breast. They are also useful in thetreatment of acute lymphoblastic and myeloblastic leukemia, Wiln'stumor, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin'slymphomas, and bronchogenic carcinoma.

[0005] Vincristine, a member of the vinca alkaloid class of oncolytics,is an isolate of a common flowering herb, the periwinkle plant (Vincarosea Linn). The mechanism of action of vincristine is still underinvestigation but has been related to the inhibition of microtubuleformation in the mitotic spindle. Vincristine is useful in the treatmentof acute leukemia, Hodgkin's disease, non-Hodgkin's malignant lymphomas,rhabdomyosarcoma, neuroblastoma, and Wilm's tumor.

[0006] Etoposide, a member of the epipodophyllotoxin class ofoncolytics, is a semisynthetic derivative of podophyllotoxin. Etoposideacts as a topoisomerase inhibitor and is useful in the therapy ofneoplasms of the testis, and lung.

[0007] It is presently unknown what determines whether a cell line willacquire resistance via a MDR1 or MRP1 mechanism. Due to the tissuespecificity of these transporters and/or in the case where one mechanismpredominates or is exclusive, it would be useful to have a selectiveinhibitor of that one over the other. Furthermore, when administering adrug or drugs that are substrates of either protein, it would beparticularly advantageous to coadminister an agent that is a selectiveinhibitor of that protein. It is, therefore, desirable to providecompounds that are selective inhibitors of MDR1 or MRP1.

SUMMARY OF THE INVENTION

[0008] The present invention relates to a compound of formula:

[0009] where:

[0010] A is a C₃-C₈ cycloalkyl, optionally substituted 1-3 times with aC₁-C₄ alkyl;

[0011] het is a five (5) membered heterocyclic ring comprising N and asecond heteroatom selected from N, O, or S;

[0012] wherein the non-fused carbon atom of the heteroaryl ring may beoptionally substituted with R^(b): C₁-C₆ alkyl, optionally substitutedaryl, optionally substituted heterocycle, an amino acid ester, CH₂OH,CH₂O-heterocycle, halo, CH₂N₃, CH₂SR¹, CH₂NR⁴R⁶, OR¹, SR¹³,S(CH₂)_(k)-phenyl, or NR⁴R⁶; provided that when het is pyrazole orimidazole, the saturated nitrogen of the het ring may be optionallysubstituted with R^(a): C₁-C₄ alkyl;

[0013] k is 0, 1, 2, 3, or 4;

[0014] n is 0, 1, or 2;

[0015] p is 0 or 1;

[0016] q is 0, 1, or 2;

[0017] r is 0, 1, or 2;

[0018] t is 0, 1, 2, 3, or 4;

[0019] u is 0, 1, 2, 3, or 4;

[0020] Y is -E-C(O)R³, -ECH═CHR¹³, -E-C(OH)R¹³, -E-NR⁴R⁵, -E-OR²,-E-S(O)_(q)R¹³, -E-SO₂NR⁴R⁶, —C(R¹¹)═NR⁶, or an optionally substitutedheterocycle;

[0021] E is a bond or —C(R¹¹)(R¹¹));

[0022] R¹ is independently at each occurrence hydrogen or C₁-C₆ alkyl;

[0023] R² is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₄alkyl)aryl, optionally substituted aryl, or optionally substitutedheterocycle, C(O)aryl, or (CH₂)₂NR⁴R⁵;

[0024] R³ is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₄alkyl)aryl, optionally substituted aryl, optionally substitutedheterocycle, OR¹³, or NR⁴R⁶;

[0025] R⁴ is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted (C₁-C₆ alkyl)-aryl, optionally substituted aryl,or R⁴ and R⁵, R⁶, R^(6′) combine to form ═CR¹R¹⁴;

[0026] R⁵ is independently at each occurrence hydrogen, C₁-C₆ alkyl,C₁-C₄ alkoxy, optionally substituted heterocycle, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀ bicycloalkyl; optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted (C₁-C₄ alkyl)-heterocycle, C(O)C(O)R¹³, C(O)R⁷, CH₂R⁷,SO₂R⁸, a moiety of the formula

[0027]  or R⁴ and R⁵, together with the nitrogen to which they areattached, combine to form an optionally substituted N-heterocycle;

[0028] R⁶ is independently at each occurrence hydrogen, C₁-C₆ alkyl,C₁-C₄ alkoxy, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₆-C₁₀ bicycloalkyl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted heterocycle, or R⁴ and R⁶,together with the nitrogen to which they are attached, combine to forman optionally substituted N-heterocycle;

[0029] R^(6′) is independently at each occurrence hydrogen, C₁-C₆ alkyl,C₁-C₄ alkoxy, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₆-C₁₀ bicycloalkyl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted heterocycle, (C₁-C₄alkyl)-OR¹³:

[0030] wherein the (C₁-C₄ alkyl) of the (C₁-C₄ alkyl)-OR¹³ may beoptionally substituted from 1 to 2 times with C₁-C₄ alkyl, optionallysubstituted aryl, optionally substituted heterocycle;

[0031] or R⁴ and R^(6′), together with the nitrogen to which they areattached, combine to form an optionally substituted N-heterocycle;

[0032] R⁷ is independently at each occurrence optionally substitutedC₁-C₆ alkyl, C₁-C₆ alkoxy, (C₁-C₄ alkoxy)-aryl, (C₁-C₄alkoxy)heterocycle, (C₁-C₄ alkoxy)-SiCH₃, optionally substituted (C₃-C₈cycloalkyl), optionally substituted (C₁-C₄ alkyl)-(C₃-C₈ cycloalkyl),optionally substituted (C₁-C₄ alkyl)aryl, optionally substituted aryl,diphenylmethyl, optionally substituted (C₁-C₄ alkyl)-CO-aryl, optionallysubstituted CO-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle,optionally substituted CH═CH— heterocycle, optionally substitutedphenoxy, optionally substituted heterocycle, optionally substituted(C₁-C₄ alkyl)-phenoxy, (CH₂)_(t)S(O)_(r)R¹, (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), (CH₂)_(t)C(R¹²)(R⁹)O(R¹⁷),(CH₂)_(t)C(R¹²)(R⁹)S(R¹⁷), or NR⁴R^(6′);

[0033] R⁸ is independently at each occurrence optionally substitutedC₁-C₆ alkyl, optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle, oroptionally substituted heterocycle;

[0034] R⁹ is independently at each occurrence hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl,optionally substituted heterocycle, (CH₂)_(u)C₁-C₆ alkoxy), optionallysubstituted (CH₂)_(u)—O—(C₃-C₈ cycloalkyl), optionally substituted(CH₂)_(u)—(C₁-C₄ alkoxy)-aryl, optionally substituted (CH₂)_(u)—O-aryl,optionally substituted (CH₂)_(u)—O-heterocycle, (C₁-C₄ alkyl)-CO₂—(C₁-C₆alkyl), optionally substituted (C₁-C₄ alkyl)-CO₂—(C₃-C₈ cycloalkyl),optionally substituted (C₁-C₄ alkyl)-CO₂—(C₁-C₄ alkyl)-aryl, optionallysubstituted (C₁-C₄ alkyl)-CO₂-aryl, optionally substituted (C₁-C₄alkyl)-CO₂-heterocycle, or R⁹ and R¹² can combine to form a C₃-C₈cycloalkyl;

[0035] R¹⁰ is 0 to 4 substituents from the aryl ring independently ateach occurrence hydrogen, halo, C(O)R³, cyano, optionally substitutedheterocycle, optionally substituted aryl, C—R¹, C₁-C₄ alkoxy, (C₁-C₄alkyl)-phenyl, NR¹⁹R²⁰, or C₂-C₆ alkenyl;

[0036] R¹¹ is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted heterocycle, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted aryl, or optionallysubstituted (C₁-C₄ alkyl)-aryl;

[0037] R¹² is independently at each occurrence hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted (C₁-C₄ alkyl)aryl, optionally substituted aryl,optionally substituted (C₁-C₄ alkyl)-heterocycle or optionallysubstituted heterocycle;

[0038] R¹³ is independently at each occurrence hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted (C₁-C₄ allyl)aryl, optionally substituted aryl,CO₂CH₂CO₂CH₂CH₃, or optionally substituted heterocycle;

[0039] R¹⁴ is independently at each occurrence C₁-C₆ alkyl or optionallysubstituted (C₁-C₄ alkyl)-aryl;

[0040] R¹⁵ is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀bicycloalkyl, optionally substituted (C₁-C₄ alkyl)aryl, optionallysubstituted aryl, optionally substituted (C₁-C₄ alkyl)heterocycle,optionally substituted heterocycle, C(O)OR¹³, SO₂R⁸, C(O)R¹⁸, or amoiety of the formula

[0041] R¹⁶ is independently at each occurrence hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted aryl, optionallysubstituted heterocycle, SO₂R⁸, or —COR⁸; or R¹⁶ and R¹⁵, together withthe nitrogen to which they are attached, combine to form an optionallysubstituted N-heterocycle;

[0042] R¹⁷ is independently at each occurrence hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted (C₁₋₄ alkyl)-aryl, optionally substituted aryl,COR¹⁸, optionally substituted heterocycle, optionally substituted (C₁-C₄alkyl)-heterocycle, optionally substituted C₁-C₆ alkoxy, optionallysubstituted (C₁-C₄ alkoxy)-aryl, optionally substituted (C₁-C₄alkoxy)heterocycle, (C₁-C₄ alkyl)-N(R¹)(R¹), or an amino acid ester;

[0043] R¹⁸ is independently at each occurrence hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl,optionally substituted (C₁-C₄ alkyl)aryl, optionally substituted aryl,optionally substituted heterocycle, (C₁-C₄ alkyl)-NHCO₂—(C₁-C₄ alkyl),or optionally substituted (C₁-C₄ alkyl)-heterocycle;

[0044] R¹⁹ is independently at each occurrence hydrogen, or optionallysubstituted C₁-C₆ alkyl;

[0045] R²⁰ is independently at each occurrence hydrogen, optionallysubstituted C₁-C₆ alkyl, CH₂OH, CO—(C₁-C₄ alkyl); or a pharmaceuticalsalt thereof.

[0046] The present invention further relates to a method of inhibitingMRP1 in a mammal which comprises administering to a mammal in needthereof an effective amount of a compound of formula I.

[0047] In another embodiment, the present invention relates to a methodof inhibiting a resistant neoplasm, or a neoplasm susceptible toresistance in a mammal which comprises administering to a mammal in needthereof an effective amount of a compound of formula I in combinationwith an effective amount of an oncolytic agent.

[0048] The present invention also relates to a pharmaceuticalformulation comprising a compound of formula I in combination with oneor more oncolytics, pharmaceutical carriers, diluents, or excipientstherefor.

DETAILED DESCRIPTION OF THE INVENTION

[0049] The current invention concerns the discovery that compounds offormula I are selective inhibitors of multidrug resistant protein(MRP1), and are thus useful in treating MRP1 conferred multidrugresistance (MDR) in a resistant neoplasm and a neoplasm susceptible toresistance.

[0050] The terms “inhibit” as it relates to MRP1 and “inhibiting MRP1”refer to prohibiting, alleviating, ameliorating, halting, restraining,slowing or reversing the progression of, or reducing MRP1's ability toredistribute an oncolytic away from the oncolytic's site of action, mostoften the neoplasm's nucleus, and out of the cell. Additionally, theseterms refer to (repeat to redistribute) an MRP1 substrate away from thesubstrate's site of action.

[0051] As used herein, the term “effective amount of a compound offormula I” refers to an amount of a compound of the present inventionwhich is capable of inhibiting MRP1. The term “effective amount of anoncolytic agent” refers to an amount of oncolytic agent capable ofinhibiting a neoplasm, resistant or otherwise.

[0052] The term “inhibiting a resistant neoplasm, or a neoplasmsusceptible to resistance” refers to prohibiting, halting, restraining,slowing or reversing the progression of, reducing the growth of, orkilling resistant neoplasms and/or neoplasms susceptible to resistance.

[0053] The term “resistant neoplasm” refers to a neoplasm, which isresistant to chemotherapy where that resistance is conferred in part, orin total, by MRP1. Such neoplasms include, but are not limited to,neoplasms of the bladder, bone, breast, lung(small-cell), testis, andthyroid and also includes more particular types of cancer such as, butnot limited to, acute lymphoblastic and myeloblastic leukemia, Wilm'stumor, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin'slymphomas, and bronchogenic carcinoma.

[0054] A neoplasm, which is “susceptible to resistance”, is a neoplasmwhere resistance is not inherent nor currently present but can beconferred by MRP1 after chemotherapy begins. Thus, the methods of thisinvention encompass a prophylactic and therapeutic administration of acompound of formula I.

[0055] The term “chemotherapy” refers to the use of one or moreoncolytic agents where at least one oncolytic agent is a substrate ofMRP1. A “substrate of MRP1” is an oncolytic that binds to MRP1 and isredistributed away from the oncolytic's site of action (the nucleus ofthe neoplasm) and out of the cell, thus, rendering the therapy lesseffective. Preferred oncolytic agents are camptosar, vinorelbine,mitoxantrone, doxorubicin, daunorubicin, epirubicin, vincristine, andetopsoside.

[0056] The terms “treat” or “treating” bear their usual meaning whichincludes preventing, prohibiting, alleviating, ameliorating, halting,restraining, slowing or reversing the progression, or reducing theseverity of MRP1 derived drug resistance in a multidrug resistant tumor.

[0057] In the general formulae of the present document, the generalchemical terms have their usual meanings. For example, the term “C₁-C₄alkyl” refers to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,cyclobutyl, s-butyl, and t-butyl. The term “C₁-C₆ alkyl” refers to amonovalent, straight, branched, or cyclic saturated hydrocarboncontaining from 1 to 6 carbon atoms. Additionally, the term “C₁-C₆alkyl” includes C₁-C₄ alkyl groups and C₃C₆ cycloalkyls. The term “C₁-C₆alkyl” includes, but is not limited to, cyclopentyl, pentyl, hexyl,cyclohexyl, and the like.

[0058] The term “C₃-C₈ cycloalkyl” refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term “C₅-C₇cycloalkyl” refers to cyclopentyl, cyclohexyl, and cycloheptyl.

[0059] The term “C₆-C₁₀ bicycloalkyl” refers to bicyclo-[2.1.1]hexanyl,[2.2.1]heptanyl, [3.2.1]octanyl, [2.2.2]octanyl, [3.2.2]nonanyl,[3.3.1]nonanyl, [3.3.2]decanyl, and [4.3.1]decanyl ring systems; andbenzofused ring systems including 1, 2, 3, 4 tetrahydronaphthalene,indane, 1,2-dihydrocyclobuta[1,2-a]benzene, andhydrocyclopropa[1,2-a]benzene.

[0060] The terms “optionally substituted C₁-C₄ alkyl” and “optionallysubstituted C₁-C₆ alkyl” refers to a C₁-C₄ alkyl or C₁-C₆ alkyl,respectively, unsubstituted or substituted from 1 to 3 times with halo,C₁-C₄ alkanol, NH₂, or hydroxy.

[0061] The terms “C₁-C₄ alkoxy” and “C₁-C₆ alkoxy” refer to moieties ofthe formula O—(C₁-C₄ alkyl) and O—(C₁-C₆ alkyl) respectively.

[0062] The term “optionally substituted C₃-C₈ cycloalkyl” refers to aC₃-C₈ cycloalkyl unsubstituted or substituted once with a phenyl,substituted phenyl, hydroxy, or CO₂R¹ group.

[0063] The terms “optionally substituted (C₁-C₄ alkyl)(C₃-C₈cycloalkyl)” refers to optionally substituted C₃-C₈ cycloalkyl linkedthrough an optionally substituted C₁-C₄ alkyl.

[0064] The term “optionally substituted O—(C₃-C₈ cycloalkyl)” refers toan optionally substituted C₃-C₈ cycloalkyl linked through an oxygenatom.

[0065] The term “optionally substituted C₆-C₁₀ bicycloalkyl” refers to aC₆-C₁₀ bicycloalkyl unsubstituted or substituted once with a phenyl,substituted phenyl, or CO₂R¹ group.

[0066] The term “halo” or “halide” refers to fluoro, chloro, bromo, andiodo.

[0067] The term “aryl” refers to phenyl, and naphthyl.

[0068] The term “optionally substituted aryl” refers to a phenyl andnaphthyl group, respectively, unsubstituted or substituted from 1 to 5times independently with C₁-C₆ alkyl, C₁-C₄ alkoxy, halo, hydroxy,trifluoromethyl, phenyl, phenoxy, SO₂R¹, OR¹; NR⁴R⁵, SO₂N(R¹³)₂, NH-Pg,C₁-C₆ alkoxy, benzyloxy, C(O)R¹³, C₅-C₇ cycloalkyl, trifluoromethoxy,SR¹, cyano, or nitro.

[0069] The term “optionally substituted (C₁-C₄ alkyl)-aryl” refers tooptionally substituted aryl linked through an optionally substitutedC₁-C₄ alkyl.

[0070] The term “optionally substituted O-aryl” refers to an optionallysubstituted aryl linked through an oxygen atom.

[0071] The term “optionally substituted phenoxy” refers to a phenoxygroup unsubstituted or substituted from 1 to 3 times independently withC₁-C₆ alkyl, halo, hydroxy, trifluoromethyl, NR⁴R⁶, SO₂N(R¹³)₂, NH-Pg,C₁-C₆ alkoxy, benzyloxy, C(O)R¹³, C₅-C₇ cycloalkyl, trifluoromethoxy,cyano, or nitro.

[0072] The term “optionally substituted (C₁-C₄ alkyl)-phenoxy” refers tounsubstituted or substituted phenoxy linked through an optionallysubstituted C₁-C₄ alkyl.

[0073] The term “heterocycle” is taken to mean stable unsaturated andsaturated 3 to 6 membered rings containing from 1 to 4 heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur, saidrings being optionally benzofused. All of these rings may be substitutedwith up to three substituents independently selected from the groupconsisting of halo, C₁-C₄ alkoxy, C₁-C₄ alkyl, cyano, nitro, hydroxy,—S(O)_(m)—(C₁-C₄ alkyl) and —S(O)_(m)-phenyl where m is 0, 1 or 2.Saturated rings include, for example, pyrrolidinyl, azetidine,piperidinyl, piperazinyl, tetrahydrofuryl, oxazolidinyl, morpholino,dioxanyl, pyranyl, and the like. Benzofused saturated rings includeindolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyland the like. Unsaturated rings include furyl, thienyl, pyridinyl,pyrrolyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, pyrimidinyl, pyrazinyl,thiophenyl, pyridazinyl, and the like. Benzofused unsaturated ringsinclude isoquinolinyl, benzoxazolyl, benzthiazolyl, quinolinyl,benzofuranyl, thionaphthyl, flranopyridine, cinnolinyl,thiophenopyridine, indolyl and the like.

[0074] The term “heteroaryl” is taken to mean an unsaturated orbenzofused unsaturated heterocycle as defined in the previous paragraph.

[0075] The term “optionally substituted heterocycle” refers to aheterocyclic ring unsubstituted or substituted 1 or 3 timesindependently with a C₁-C₆ alkyl, halo, benzyl, optionally substitutedphenyl, SR¹, C₁-C₄ alkoxy, CO₂R¹, nitro, cyano, (C₁-C₄ alkyl)-cyano,heterocycle, NR¹⁹R²⁰, COR¹², C₁-C₆ alkanol, benzyloxy, phenoxy,trifluoromethyl. Heterocyclic rings may be additionally substituted 1 or2 times with an oxo group.

[0076] The term “optionally substituted O-heterocycle” refers to anoptionally substituted heterocycle linked through an oxygen atom.

[0077] The term “optionally substituted (C₁-C₄ alkyl)-heterocycle”refers to optionally substituted heterocycle linked through anoptionally substituted C₁-C₄ alkyl. The term “N-heterocycle” refers to anitrogen containing heterocycle linked through a nitrogen atom.

[0078] The term “optionally substituted N-heterocycle” refers to aN-heterocycle, optionally substituted 1 or 3 times independently with aC₁-C₆ alkyl, halo, benzyl, optionally substituted phenyl, SR¹, C₁-C₄alkoxy, CO₂R¹, nitro, cyano, (C₁-C₄ alkyl)-cyano, heterocycle, NR¹⁹R²⁰,COR¹², C₁-C₆ alkanol, benzyloxy, phenoxy, trifluoromethyl; andadditionally substituted 1 or 2 times with an oxo group.

[0079] The term “amino acid ester” as used in this specification refersto an amino acid, where the carboxy group is substituted with a C₁-C₆alkyl or benzyl group. That is, the alkyl group when taken together withthe carboxy group forms a C₁-C₆ alkyl ester. A skilled artisan wouldappreciate that some amino acids have two carboxy groups that may besubstituted with a C₁-C₆ alkyl group, for example, aspartic acid andglutamic acid.

[0080] This invention contemplates the possibility of amino acid mono-or diesters in these circumstances.

[0081] The term “amino acid” refers to a chemical unit made up of both abasic amino group and an acidic carboxyl group. Examples of amino acidsinclude alanine, asparagine, cysteine, glutamine, glycine, isoleucine,leucine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine, valine, aspartic acid, glutamic acid, arginine,histidine, and lysine.

[0082] The term “protecting group” (Pg) refers to an amino protectinggroup or a hydroxy protecting group. The species of protecting groupwill be evident from whether the “Pg” group is attached to a nitrogenatom (amino protecting group) or attached to an oxygen atom (hydroxyprotecting group).

[0083] The term “amino protecting group” as used in this specificationrefers to a substituent(s) of the amino group commonly employed to blockor protect the amino functionality while reacting other functionalgroups on the compound. Examples of such amino-protecting groups includethe formyl group, the trityl group, the phthalimido group, the acetylgroup, the trichloroacetyl group, the chloroacetyl, bromoacetyl, andiodoacetyl groups, urethane-type blocking groups such asbenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (“BLOC”), and the like;and like amino protecting groups. The species of amino protecting groupemployed is not critical so long as the derivitized amino group isstable to the condition of subsequent reaction(s) on other positions ofthe molecule and can be removed at the appropriate point withoutdisrupting the remainder of the molecule. Similar amino protectinggroups used in the cephalosporin, penicillin, and peptide arts are alsoembraced by the above terms. Further examples of groups referred to bythe above terms are described by T. W. Greene, “Protective Groups inOrganic Synthesis”, John Wiley and Sons, New York, N.Y., 1991, Chapter 7hereafter refereed to as “Greene”. A preferred amino protecting group ist-butyloxycarbonyl.

[0084] The term “hydroxy protecting group” denotes a group understood byone skilled in the organic chemical arts of the type described inChapter 2 of Greene. Representative hydroxy protecting groups include,for example, ether groups including methyl and substituted methyl ethergroups such as methyl ether, methoxymethyl ether, methylthiomethylether, tert-buylthiomethyl ether, (phenyldimethylsilyl)methoxy-methylether, benzyloxymethyl ether, p-methoxybenzyloxy-methyl ether, andtert-butoxymethyl ether, substituted ethyl ether groups such asethoxyethyl ether, 12-chloroethoxy)-ethyl ether,2,2,2-trichloroetboxymethyl ether, and 2-(trimethylsilyl)ethyl ether,isopropyl ether groups; phenyl and substituted phenyl ether groups suchas phenyl ether, p-chlorophenyl ether, p-methoxyphenyl ether, and2,4-dinitrophenyl ether; benzyl and substituted benzyl ether groups suchas benzyl ether, p-methoxybenzyl ether, onitrobenzyl ether, and2,6-dichlorobenzyl ether, and alkylsilyl ether groups such astrimethyl-triethyl- and triisopropylsilyl ethers, mixed alkylsilyl ethergroups such as dimethylisopropylsilyl ether, and diethylisopropylsilylether; and ester protecting groups such as formate ester, enzylformateester, mono-, di-, and trichloroacetate esters, phenoxyacetate ester,and p-chlorophenoxyacetate and the like. The species of hydroxyprotecting group employed is not critical so long as the derivatizedhydroxy group is stable to the conditions of subsequent reaction(s) onother positions of the intermediate molecule and can be selectivelyremoved at the appropriate point without disrupting the remainder of themolecule including any other hydroxy protecting group(s).

[0085] The term “carbonyl activating group” refers to a substituent of acarbonyl that increases the susceptibility-of-that carbonyl tonucleophilic-addition. Such groups include, but are not limited to,alkoxy, aryloxy, nitrogen containing unsaturated heterocycles, or aminogroups such as oxybenzotriazole, imidazolyl, nitrophenoxy,pentachloro-phenoxy, N-oxysuccinimide, N,N′-dicyclohexylisoure-O-yl,N-hydroxy-N-methoxyamino, and the like; acetates, formates, sulfonatessuch as methanesulfonate, ethanesulfonate, benzenesulfonate, orp-toluenylsulfonate, and the like; and halides especially chloride,bromide, or iodide.

[0086] The term “carbonyl activating reagent” refers to a reagent thatconverts the carbonyl of a carboxylic acid group to one that is moreprone to nucleophilic addition and includes, but is not limited to, suchreagents as those found in “The Peptides”, Gross and Meienhofer, Eds.,Academic Press (1979), Ch. 2 and M. Bodanszky, “Principles of PeptideSynthesis”, 2^(nd) Ed., Springer-Verlag Berlin Heidelberg, 1993,hereafter referred to as “The Peptides” and “Peptide Synthesis”respectively. Specifically, carbonyl activating reagents include thionylbromide, thionyl chloride, oxalyl chloride, and the like; alcohols suchas nitrophenol, pentachlorophenol, and the like; amines such asN-hydroxy-N-methoxyamine and the like; acid halides such as acetic,formic, methanesulfonic, ethanesulfonic, benzenesulfonic, orp-tolylsulfonic acid halide, and the like; and compounds such as1,1′-carbonyldiimidazole, benzotriazole, imidazole,N-hydroxysuccinimide, dicyclohexylcarbodiimide, and the like.

[0087] In general, the term “pharmaceutical” when used as an adjectivemeans substantially non-toxic to living organisms. For example, the term“pharmaceutical salt” as used herein, refers to salts of the compoundsof formula I which are substantially non-toxic to living organisms. See,e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., “PharmaceuticalSalts”, J. Pharm Sci., 66:1, 1977. Typical pharmaceutical salts includethose salts prepared by reaction of the compounds of formula I with aninorganic or organic acid or base. Such salts are known as acid additionor base addition salts, respectively. These pharmaceutical saltsfrequently have enhanced solubility characteristics compared to thecompound from which they are derived, and thus are often more amenableto formulation as liquids or emulsions.

[0088] The term “acid addition salt” refers to a salt of a compound offormula I prepared by reaction of a compound of formula I with a mineralor organic acid. For exemplification of pharmaceutical acid additionsalts see, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J.Pharm. Sci., 66:1, 1977. Since compounds of this invention can be basicin nature, they accordingly react with any of a number of inorganic andorganic acids to form pharmaceutical acid addition salts.

[0089] The pharmaceutical acid addition salts of the invention aretypically formed by reacting the compound of formula I with an equimolaror excess amount of acid. The reactants are generally combined in amutual solvent such as diethylether, tetrahydrofuran, methanol, ethanol,isopropanol, benzene, and the like. The salts normally precipitate outof solution within about one hour to about ten days and can be isolatedby filtration or other conventional methods.

[0090] Acids commonly employed to form acid addition salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids, such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, P-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, 1,5-naphthalenedisulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and thelike.

[0091] The term “base addition salt” refers to a salt of a compound offormula I prepared by reaction of a compound of formula I with a mineralor organic base. For exemplification of pharmaceutical base additionsalts see, e.g., Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J.Pharm. Sci., 66:1, 1977. This invention also contemplates pharmaceuticalbase addition salts of compounds of formula I The skilled artisan wouldappreciate that some compounds of formula I may be acidic in nature andaccordingly react with any of a number of inorganic and organic bases toform pharmaceutical base addition salts. Examples of pharmaceutical baseaddition salts are the ammonium, lithium, potassium, sodium, calcium,magnesium, methylamino, diethylamino, ethylene diamino, cyclohexylamino,and ethanolamino salts, and the like of a compound of formula I.

[0092] While all of the compounds of the present invention are useful,certain of the compounds are particularly interesting and are preferred.The following listing sets out several groups of preferred compounds. Itwill be understood that each of the listings may be combined with otherlistings to create additional groups of preferred embodiments.

[0093] i. A is C₅-C₆ cycloalkyl;

[0094] ii. A is cyclopentyl;

[0095] iii. A is cyclohexyl;

[0096] iv. R^(b) is C₁-C₆ alkyl;

[0097] v. R^(b) is methyl;

[0098] vi. R^(b) is halo;

[0099] vii. n is 0:

[0100] viii. n is 1;

[0101] ix. p is 0;

[0102] x. p is 1;

[0103] xi. Y is -E-C(O)R³, -E-NR⁴R⁵, or an optionally substitutedheterocycle;

[0104] xii. Y is -EC(O)R³;

[0105] xiii. Y is -E-NR⁴R⁵;

[0106] xiv. Y is an optionally substituted heterocycle;

[0107] xv. E is a bond;

[0108] xvi. When Y is -E-C(O)R³, R³ is OR¹³, or NR⁴R⁶;

[0109] xvii. When Y is -E-C(O)R³, R³ is OR¹³, R¹³ is optionallysubstituted C₁-C₆ alkyl;

[0110] xviii. When Y is -E-C(O)R³, R³ is OR¹³, R¹³ is methyl;

[0111] xix. When Y is -E-C(O)R³, R³ is OR¹³, R¹³ is optionallysubstituted (C₁-C₄ alkyl)-aryl;

[0112] xx. When Y is -E-C(O)R³, R³ is OR¹³ and R¹³ is benzyl;

[0113] xxi. When Y is -E-C(O)R³, R³ is OR¹³ and R¹³ is optionallysubstituted aryl;

[0114] xxii. When Y is -E-C(O)R³, R³ is OR¹³ and R¹³ is phenyl;

[0115] xxiii. When Y is -E-C(O)R³, R³ is NR⁴R⁶ and R⁴ is hydrogen;

[0116] xxiv. When Y is -E-C(O)R³, R³ is NR⁴R⁶, R⁴ is hydrogen, and R⁶ isC₁-C₆ alkyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₆-C₁₀ bicycloalkyl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-heterocycle, or optionally substituted heterocycle;

[0117] xxv. When Y is -E-C(O)R³, R³ is NR⁴R⁶, R⁴ and R⁶, together withthe nitrogen to which they are attached, combine to form an optionallysubstituted N-heterocycle;

[0118] xxvi. When Y is -E-NR⁴R⁵, R⁴ is hydrogen;

[0119] xxvii. When Y is -E-NR⁴R⁵, R⁴ is hydrogen, and R⁵ is C(O)R⁷;

[0120] xxviii. When Y is -E-NR⁴R⁵, R⁴ is hydrogen, and R⁵ is C(O)R⁷, R⁷is C₁-C₆ alkoxy, optionally substituted (C₃-C₈ cycloalkyl), optionallysubstituted (C₁-C₄ alkyl)-(C₃-C₈ cycloalkyl), optionally substituted(C₁-C₄ alkyl)-aryl, optionally substituted aryl, diphenylmethyl,optionally substituted (C₁-C₄ alkyl)-CO-aryl, optionally substitutedCO-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle, optionallysubstituted heterocycle, (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), or(CH₂)_(t)C(R¹²)(R⁹)O(R¹⁷);

[0121] xxix. When Y is -E-NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, and R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵);

[0122] xxx. When Y is -E-NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R⁵), R¹² is hydrogen, and R⁹ is phenyl;

[0123] xxxi. When Y is -E-NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), R¹² is hydrogen, R⁹ is phenyl, and R¹⁶is hydrogen, then R¹⁵ is hydrogen, C₁-C₆ alkyl, optionally substitutedC₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀ bicycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted (C₁-C₄ alkyl)heterocycle, optionally substitutedheterocycle, C(O)OR¹³, SO₂R⁸, or C(O)R¹⁸;

[0124] xxxii. When Y is -E-NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), R¹² is hydrogen, R⁹ is phenyl, and R¹⁶is hydrogen, then R¹⁵ is optionally substituted phenyl;

[0125] xxxiii. When Y is -E-NR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵), R¹² is hydrogen, R⁹ is phenyl, and R¹⁶is hydrogen, then R¹⁵ is optionally substituted heterocycle

[0126] xxxiv. When Y is -ENR⁴R⁵, R⁴ is hydrogen, R⁵ is C(O)R⁷, R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵) R¹² is hydrogen, and R⁹ is phenyl, thenR¹⁶ and R¹⁵, together with the nitrogen to which they are attached,combine to form an optionally substituted N-heterocycle;

[0127] xxxv. When Y is -E-NR⁴R⁵, R⁴ and R⁵, together with the nitrogento which they are attached, combine to form an optionally substitutedN-heterocycle;

[0128] xxxvi. R⁴ is hydrogen

[0129] xxxvii. R⁴ is C₁-C₆ alkyl;

[0130] xxxviii. R⁵ is hydrogen;

[0131] xxxix. R⁵ is optionally substituted heterocycle;

[0132] xl. R⁵ is optionally substituted C₆-C₁₀ bicycloalkyl;

[0133] xli. R⁵ is optionally substituted (C₁-C₄ alkyl)aryl;

[0134] xlii. R⁵ is SO₂R⁸;

[0135] xliii. R⁵ is a moiety of the formula

[0136] xliv. R⁶ is hydrogen;

[0137] xlv. R⁶ is C₁₋₆ alkyl;

[0138] xlvi. R⁶ is optionally substituted C₃-C₈ cycloalkyl;

[0139] xlvii. R⁶ is optionally substituted C₆-C₁₀ bicycloalkyl;

[0140] xlviii. R⁶ is optionally substituted (C₁-C₄ alkyl)aryl;

[0141] xlix. R⁶ is optionally substituted aryl;

[0142] l. R⁶ is optionally substituted (C₁-C₄ alkyl)heterocycle;

[0143] li. R⁶ is optionally substituted heterocycle;

[0144] lii. R^(6′) is C₁-C₆alkyl;

[0145] liii. R^(6′) is optionally substituted C₃-C₈ cycloalkyl;

[0146] liv. R^(6′) is optionally substituted C₆-C₁₀ bicycloalkyl;

[0147] lv. R^(6′) is optionally substituted (C₁-C₄ alkyl)aryl;

[0148] lvi. R^(6′) is optionally substituted aryl;

[0149] lvi. R⁷ is optionally substituted C₁₋₆ alkyl;

[0150] lviii. R⁷ is C₁₋₆ alkoxy;

[0151] lix. R⁷ is (C₁-C₄ alkoxy)-aryl;

[0152] lx. R⁷ is optionally substituted (C₃-C₈ cycloalkyl);

[0153] lxi. R⁷ is optionally substituted (C₁-C₄ alkyl)(C₃-C₈cycloalcyl);

[0154] lxii. R⁷ is optionally substituted (C₁-C₄ alkyl)-aryl;

[0155] xiii. R⁷ is optionally substituted aryl;

[0156] lxiv. R⁷ is diphenylmethyl;

[0157] lxv. R⁷ is optionally substituted (C₁-C₄ alkyl)-CO-aryl;

[0158] lxvi. R⁷ is optionally substituted CO-aryl;

[0159] lxvii. R⁷ is optionally substituted (C₁-C₄ alkyl)-heterocycle;

[0160] lxviii. R⁷ is optionally substituted phenoxy;

[0161] lxix. R⁷ is optionally substituted heterocycle;

[0162] lxx. R⁷ is (CH₂)_(t)S(O)_(r)R¹;

[0163] lxxi. R⁷ is (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵);

[0164] lxxii. R⁷ is (CH₂)_(t)C(R¹²)(R⁹)O(R¹⁷);

[0165] lxxiii. R⁷ is (CH₂)_(t)C(R¹²)(R⁹)S(R¹⁷);

[0166] lxxiv. R⁷ is NR⁴R⁶′;

[0167] lxxv. R⁸ is optionally substituted C₁-C₆ alkyl;

[0168] lxxvi. R⁸ is optionally substituted aryl;

[0169] lxxvii. R⁸ is optionally substituted (C₁-C₄ alkyl)-aryl;

[0170] lxxviii. R⁹ is hydrogen;

[0171] lxxix. R⁹ is optionally substituted C₁-C₆ alkyl;

[0172] lxxx. R⁹ is optionally substituted C₃-C₈ cycloalkyl;

[0173] lxxxi. R⁹ is optionally substituted aryl;

[0174] lxxxii. R⁹ is optionally substituted heterocycle;

[0175] lxxxiii. R⁹ is optionally substituted (CH₂)_(u)—(C₁-C₄alkoxy)-aryl;

[0176] lxxxiv. R⁹ and R¹² combine to form a C₃-C₈ cycloalkyl;

[0177] lxxxv. R¹⁰ is 1 to 4 substituents selected from the groupconsisting of hydrogen, halo, cyano, optionally substituted heterocycle,or NR¹⁹R²⁰;

[0178] lxxxvi. R¹⁰ is monosubstituted with chloro;

[0179] lxxxvii. R¹⁰ is monosubstituted with cyano;

[0180] lxxxviii. R¹⁰ is monosubstituted with NH₂;

[0181] lxxxix. R¹¹ is hydrogen;

[0182] xc. R¹² is hydrogen;

[0183] xci. R¹² is optionally substituted C₁-C₆ alkyl;

[0184] xcii. R¹² is optionally substituted aryl;

[0185] xciii R¹³ is hydrogen;

[0186] xciv. R¹³ is optionally substituted C₁-C₆ alkyl;

[0187] xcv. R¹³ is optionally substituted (C₁-C₄ alkyl)-aryl;

[0188] xcvi. R¹³ is optionally substituted aryl;

[0189] xcvii. R¹³ is CO₂CH₂CO₂CH₂CH₃;

[0190] xcviii. R¹⁵ is hydrogen;

[0191] xcix. R¹⁵ is C₁-C₆;

[0192] c. R¹⁵ is optionally substituted C₆-C₁₀ bicycloalkyl;

[0193] ci. R¹⁵ is optionally substituted aryl;

[0194] cii. R¹⁵ is optionally substituted heterocycle;

[0195] ciii. R¹⁵ is C(O)OR¹³;

[0196] civ. R¹⁵ is SO₂R⁸;

[0197] cv. R¹⁵ is C(O)R¹⁸;

[0198] cvi. R¹⁶ is hydrogen;

[0199] cvii. R¹⁶ is optionally substituted C₁-C₆ alkyl;

[0200] cviii. R¹⁶ and R¹⁵, together with the nitrogen to which they areattached, combine to form an optionally substituted N-heterocycle;

[0201] cix. R¹⁷ is hydrogen;

[0202] cx. R¹⁷ is optionally substituted C₁-C₆ alkyl;

[0203] cxi. R¹⁷ is optionally substituted aryl;

[0204] cxii. R¹⁷ is optionally substituted heterocycle;

[0205] cxiii. R¹⁸ is hydrogen;

[0206] cxiv. R¹⁸ is optionally substituted C₁-C₆ alkyl;

[0207] cxv. R¹⁸ is optionally substituted aryl;

[0208] cxvi. R¹⁸ is optionally substituted heterocycle;

[0209] cxvii. R¹⁸ is (C₁-C₄ alkyl)-NHCO₂—(C₁-C₄ alkyl);

[0210] cxviii. R¹⁹ is hydrogen;

[0211] cxix. R¹⁹ is optionally substituted C₁₋₆ alkyl;

[0212] cxx. R²⁰ is hydrogen;

[0213] cxxi. R²⁰ is optionally substituted C₁-C₆ alkyl;

[0214] cxxii. R²⁰ is CH₂OH;

[0215] cxxiii. R²⁰ is CO—(C₁-C₄ alkyl);

[0216] cxxiv. Het is R

[0217] cxx. Het is

[0218] cxxvi. Het is

[0219] cxxvii. Het is

[0220] cxxvii. Het is

[0221] cxxix. Het is

[0222] cxxx. Het is

[0223] cxxxi. R^(b) is chloro;

[0224] cxxxii. R^(a) is hydrogen;

[0225] cxxxiii. R^(a) is t-butyl;

[0226] cxxxiv. The compound is a pharmaceutical salt; and

[0227] cxxxv. The compound is the hydrochloride salt.

[0228] The following group, including the racemic trans and cis, and theisolated enantiomers, is illustrative of compounds contemplated withinthe scope of this invention:

[0229] a)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-3-2-hydroxy-acetamide

[0230] b)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-hydroxy-3-methyl-butyramide

[0231] c)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-3-hydroxy-3-phenyl-propionamide

[0232] d)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-3-hydroxy-3-phenyl-propionamide

[0233] e) N-[3-(9-Chloro-3-methyloxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-3-methyl-butyramide

[0234] f) 1-Hydroxy-cyclopropanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

[0235] g){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-methyl}-methyl-carbamicacid tert-butyl ester

[0236] h)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-methylamino-acetamidehydrochloride

[0237] i)N-[3-(9-Chloro-3-methy]4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-acetamide

[0238] j){1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0239] k)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-methyl-propionamidehydrochloride

[0240] l){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-methyl}-carbamicacid tert-butyl ester

[0241] m)2-Amino-N-[39-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamidehydrochloride

[0242] n) 2-Hydroxy-hexanoic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

[0243] o)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-hydroxy-benzamide

[0244] p)4-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-piperazine-1-carboxylicacid tert-butyl ester

[0245] q)N-[349-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-phenyl-2-piperazin-1-yl-acetamidedihydrochloride

[0246] r) {[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-phenyl-methyl}-methyl-carbamic acid tert-butylester

[0247] s)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-methylamino-2-phenyl-acetamidehydrochloride

[0248] t)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-[4(2-hydroxy-ethyl)-piperazin-1-yl]-2-phenyl-acetamide

[0249] u)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-phenyl-2-(4-pyridin-2-yl-piperazin-1-yl)-acetamide

[0250] v)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-piperidin-1-yl-acetamide

[0251] w)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(4-methyl-piperazin-1-yl)-acetamide

[0252] x)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-diethylamino-acetamide

[0253] y)2-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-6-methoxy-isonicotinamide

[0254] z)3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid (2-hydroxy-1-phenyl-ethyl)-amide

[0255] aa) 3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylic acid (2-hydroxy-1-phenyl-ethyl)-amide

[0256] bb)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(methyl-phenyl-amino)-acetamide

[0257] cc)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-phenyl-2-(pyridin-3-yloxy)-acetamide

[0258] dd)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-3-yloxy)-acetamide

[0259] ee){1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-cyclohexyl}-carbamicacid tert-butyl ester.

[0260] ff) 1-Amino-cyclohexanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-S-yl)-cyclohexyl]-amidehydrochloride

[0261] gg)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-morpholin-4-yl-acetamide

[0262] hh)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(4-hydroxy-piperidin-1-yl)-acetamide

[0263] ii)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-2-yloxy)-acetamide

[0264] jj)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-4-yloxy)acetamide

[0265] kk)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-4-ylsulfanyl)-acetamide

[0266] ll){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-cyclohexyl-methyl}-carbamicacid tert-butyl ester

[0267] mm)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-cyclohexyl-acetamidehydrochloride

[0268] nn)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-cyclohexyl-acetamidehydrochloride

[0269] oo){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-cyclohexyl-methyl}-carbamic acid tert-butyl ester

[0270] pp) thieno[3,2-b]pyridine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-amide

[0271] qq)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl)-2-(2-chloro-pyridin-4-yloxy)-acetamide

[0272] rr)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(quinolin-3-yloxy)-acetamide

[0273] ss)2-tert-Butylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamide

[0274] tt)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-2-ylsulfanyl)acetamide

[0275] uu)(2-aminoindan-2-yl)-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]carboxamide

[0276] vv) N-[3-(9-Chloro-3-methyloxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl)-2-dimethylamino-2-cyclohexylpropionamide

[0277] ww)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-2-(3-chlorophenyl)-propionamide

[0278] xx)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-dimethylamino-2-pyrid-1-yl-propionamide

[0279] yy)N-(3-(9-Chloro-3-methyl-4-oxo-H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-dimethylamino-2-fur-3-yl-propionamide

[0280] zz)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(2-chlorophenyl)amino-2-(3-chlorophenyl)propionamide

[0281] aaa)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-diphenylamino-2-phenylpropionamide

[0282] bbb)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclobutyl]-2-hydroxy-acetamide

[0283] ccc)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-hydroxy-3-methyl-butyramide

[0284] ddd)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cycloheptyl]-3-hydroxy-3-phenyl-propionamide

[0285] eee)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclobutyl]-3-hydroxy-3-phenyl-propionamide

[0286] fff)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-hydroxy-3-methyl-butyramide

[0287] ggg) 1-Hydroxy-cyclopropanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cycloheptyl]-amide

[0288] hhh){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentylcarbamoyl]-methyl}-methyl-carbamic acid tert-butyl ester

[0289] iii)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl]-2-methylamino-acetamidehydrochloride

[0290] jjj)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-acetamide

[0291] kkk){1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-1-methyl-ethyl}-carbamicacid tert-butyl ester

[0292] lll)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-methyl-propionamidehydrochloride

[0293] mmm){[3-(9-Chloro-3-methyl-4-oxo-5]-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-methyl}-carbamicacid tert-butyl ester

[0294] nnn) 2-Amino-N-[3-(9-chloro-3-methyloxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl)-acetamidehydrochloride

[0295] ooo) 2-Hydroxy-hexanoic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-amide

[0296] ppp)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-hydroxy-benzamide

[0297] qqq)4-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-phenyl-methyl}-piperazine-1-carboxylicacid tert-butyl ester

[0298] rrr)N-(3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl]-2-phenyl-2-piperazin-1-yl-acetamidedihydrochloride

[0299] sss){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentylcarbamoyl]-phenyl-methyl}-methyl-carbamic acid tert-butylester

[0300] ttt)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-methylamino-2-phenyl-acetamidehydrochloride

[0301] uuu)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2-phenyl-acetamide

[0302] vvv)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-phenyl-2-(4-pyridin-2-yl-piperazin-1-y)-acetamide

[0303] www)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl]-2-piperidin-1-yl-acetamide

[0304] xxx)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(4-methyl-piperazin-1-yl)-acetamide

[0305] yyy)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-diethylamino-acetamide

[0306] zzz)2-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylmethyl]-6-methoxy-isonicotinamide

[0307] aaaa)3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid (2-hydroxy-1-phenyl-ethyl)-amide

[0308] bbbb)3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid (2-hydroxy-1-phenyl-ethyl)-amide

[0309] cccc)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(methyl-phenyl-amino)-acetamide

[0310] dddd)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-phenyl-2-(pyridin-3-yloxy)-acetamide

[0311] eeee)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl]-2-(pyridin-3-yloxy)-acetamide

[0312] ffff){1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-cyclopentyl}-carbamicacid tert-butyl ester.

[0313] gggg) 1-Amino-cyclohexanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl]-amidehydrochloride

[0314] hhhh)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-morpholin-4-yl-acetamide

[0315] iiii)N-[3-(9-Chloro-3-methyl-4-oxo-H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(4-hydroxy-piperidin-1-yl)-acetamide

[0316] jjjj)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(pyridin-2-yloxy)-acetamide

[0317] kkkk)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(pyridin-4-yloxy)-acetamide

[0318] llll)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl)-2-(pyridin-4-ylsulfanyl)-acetamide

[0319] mmmm){[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-cyclohexyl-methyl}-carbamicacid tert-butyl ester

[0320] nnnn)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-cyclohexyl-acetamidehydrochloride

[0321] oooo)2-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-cyclopentyl-acetamidehydrochloride

[0322] pppp){[3-(9-Chloro-3-methyl-4-oxo-5]-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylcarbamoyl]-cyclohexyl-methyl}-carbamicacid tert-butyl ester

[0323] qqqq) thieno[3,2-b]pyridine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-amide

[0324] rrrr)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(2-chloro-pyridin-4-yloxy)-acetamide

[0325] ssss)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(quinolin-3-yloxy)-acetamide

[0326] tttt)2-tert-Butylaino-N-[3-(9-chloro-3-methyl-7-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-acetamide

[0327] uuuu)N-[3-(9-Chloro-3-methyl-4-oxo-H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(pyridin-2-ylsulfanyl)-acetamide

[0328] vvvv)(2-aminoindan-2-yl)-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclopentyl]carboxamide

[0329] wwww)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-2-cyclohexylpropionamide

[0330] xxxx)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-2-(3-chlorophenyl)-propionamide

[0331] yyyy)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-2-pyrid-1-yl-propionamide

[0332] zzzz)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-dimethylamino-2-fur-3-yl-propionamide

[0333] aaaaa)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl]-2-(2-chlorophenyl)amino-2-(3-chlorophenyl)-propionamide

[0334] bbbbb)N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl]-2diphenylamino-2-phenylpropionamide

[0335] The compounds of the present invention can be prepared by avariety of procedures, some of which are illustrated in the Schemesbelow. The particular order of steps required to produce the compoundsof formula I is dependent upon the particular compound beingsynthesized, the starting compound, and the relative lability of thesubstituted moieties.

[0336] Compounds of formula I(a), wherein R^(b), the substituentattached to the non-fused carbon, is C₁-C₆ alkyl, optionally substitutedaryl, optionally substituted heterocycle, CH₂OH, or CH₂O-heterocycle maybe prepared from compounds of formula II(a) as illustrated in Scheme 1below where Y, A, R¹⁰, het, n, and p are as described supra.

[0337] Compounds of formula I(a) may be prepared by dissolving orsuspending a compound of formula II(a) in a suitable solvent, preferablydimethylformamide, and adding a suitable base, including potassiummethoxide, potassium tert-butoxide, potassium carbonate, sodiumhexamethyldisilazane, and preferably potassium hexamethyldisilazane. Thebase is typically employed in a one to one ratio. However, as theskilled artisan would appreciate, a slight molar excess, usually inabout a 1.1 to about a 3 fold molar excess relative to the compound offormula II(a), is acceptable.

[0338] The reactants are typically combined at a temperature from about0° C. to about 100° C. When het is isoxazole, oxazole, or imidazole, thereactants are preferably combined at room temperature and the resultingsolution is typically mixed for from about 5 minutes to about 18 hours,preferably from about 15 minutes to about 3 hours. When het is pyrazolethe reactants are preferably combined at room temperature and theresulting solution is typically heated to about 100° C. for about 30minutes to about 18 hours.

[0339] It is preferred, when A is cyclopentyl and the base employed ispotassium hexamethyldisilazane, to combine the reactants from about 60°C. to about 100° C. for about 3 to about 6 minutes.

[0340] Any protecting groups remaining in the cyclized compound offormula I may be removed as taught in Greene to provide additionalcompounds of formula I. Preferred choices of protecting groups andmethods for their removal may be found in the Preparations and Examplessections below.

[0341] Compounds of formula I(b), wherein bet is substituted with halomay be prepared from compounds of formula II(b) as illustrated in Scheme2 below where Y, A, R¹⁰, het, n, and p are as described supra.

[0342] Compounds of formula I(b) may be prepared by dissolving orsuspending a compound of formula II(b) in a suitable solvent and addinga suitable base, in an inert atmosphere, preferably under N₂. Typicallya preferred and convenient solvent is dimethylformamide. A preferredbase is sodium trimethylsilanolate. The base is typically employed in aslight molar excess, usually in about a 1.05 fold molar excess relativeto the compound of formula II(b). The reactants are typically combineddropwise at room temperature over a period of time from about 2 hours toabout 4 hours.

[0343] The skilled artisan would appreciate that if other bases are usedin the reaction of Scheme 2, the substituent of the het functionalitymay change. For example if sodium methylthiolate is used as thepreferred base, the compound of formula II(b) will be converted into thecompound of formula I wherein the het functionality is substituted withSCH₃.

[0344] Additionally, the compound of formula I(b) can be preparedaccording to Scheme 1 wherein the reactants are combined at about 0° C.and mixed at about −10° C. for approximately three hours. The solutionis then warmed to room temperature and mixed for an additional 2 to 3hours.

[0345] Certain compounds of formula I(c) are useful MRP1 inhibitors andare also useful intermediates for the preparation of other compounds offormula 1. As is shown in Scheme 3, when R^(b) is CH₂O-Pg, a derivativeof formula I(c) wherein Pg is a protecting group, the compound offormula I(c) may be further reacted by methods known in the art toproduce compounds of formula I(d) where R^(b′) is CH₂OH, CH₂N₃, CH₂SR¹,or CH₂NR⁴R⁶, and Y, A, het, p, n, R¹, R⁴, R⁶, and R¹⁰ are as describedsupra.

[0346] Compounds of formula I(d) wherein het is substituted with CH₂OHmay be prepared by dissolving or suspending a compound of formula I(c)in a suitable solvent and adding a suitable acid. Typically a preferredand convenient solvent is methanol/dichloromethane (2:1). A preferredacid is p-toluenesulfonic acid hydrate. The acid is typically employedin a slight molar excess, usually in about a 1.05 fold molar excessrelative to the compound of formula I(c). The reactants are typicallycombined at room temperature and mixed from about 1 hour to about 3hours.

[0347] The skilled artisan would appreciate that the alcohol can befurther converted to compounds of formula I(d) where het is substitutedwith CH₂N₃, CH₂SR¹³, or CH₂NR⁴R⁶ by methods well known in the art. Forgeneral examples of these procedures, see the Preparations and Examplesection.

[0348] Compounds of formula I(e) when het is substituted with chloro areuseful MRP1 f inhibitors and are also useful intermediates for thepreparation of other compounds of formula I. As is shown in Scheme 4,the compound of formula I(e) may be further reacted with a nucleophileby methods known in the art to produce compounds of formula I(q) wherehet is substituted with an amino acid ester, OR¹, SR¹³,S(CH₂)_(k)-phenyl, NR⁴R⁶, or an optionally substituted heterocycleattached via a heteroatom, and Y, A, p, n, k, het, R¹, R⁴, R⁶, R¹⁰, andR¹³ are as described supra.

[0349] Compounds of formula I(q) may be prepared by dissolving orsuspending a compound of formula I(e) in a suitable solvent and addingan appropriate nucleophile, in an inert atmosphere, preferably under N₂.Typically a preferred and convenient solvent is dimethylformamide. Thenucleophile is typically employed in a molar excess, usually in about a2 to about a 4 fold molar excess relative to the compound of formulaI(e).

[0350] The reactants are preferably combined at room temperature and theresulting solution is typically mixed for about 30 minutes to about 3hours, until the reaction is complete as measured by the consumption ofthe substrate. The skilled artisan would appreciate that the reaction,depending on the nucleophile used, may require more time to react andmay, also require heating. In these instances, it is preferred to mixthe reactants for approximately 15 to approximately 20 hours, then heatthe solution from about 50° C. to about 80° C. and mix for an additional3 hours or until the reaction is complete as measured by the consumptionof the compound of formula I(e).

[0351] Compounds of formula I(p) where Y is C(R^(11′))(R¹¹)NR⁴R⁵ may beprepared from compounds of formula I(n) as illustrated in Scheme 5 belowwhere R³ and R¹¹ are equivalent, R^(11′) is H, and het, n, p, A, R⁴, R⁵,and R¹⁰ are as described supra.

[0352] The compounds of formula I(n) may be reductively aminated to formthe compounds of formula I(p). Reductive aminations are well knowntransformations, see, e.g., Larock, “Comprehensive OrganicTransformations”, pg. 421, VCH Publishers, New York, N.Y., 1989,hereafter referred to as “Larock”.

[0353] Amines of formula III may be dissolved or suspended in a suitablesolvent, preferably methanol, optionally in the presence of a suitablebase, preferably N-methyl morpholine or triethylamine. When the compoundof formula III is an acid addition salt, it is preferred to convert thesalt to its free amine form. A compound of formula I(n) is then added tothe mixture. Optionally, a Lewis acid catalyst, such as titanium(IV)isopropoxide, may be employed. Once the compound of formula I(n) hasbeen substantially consumed, the intermediate is typically reacted insitu with a suitable reducing agent to provide the compounds of formulaI(p). The overall conversion may be performed at about 0° C. to theboiling point of the mixture, but room temperature is a preferredreaction temperature. The formation of the compounds of formula I(p) maytake from 15 minutes to 24 hours as measure by the consumption of thesubstrate.

[0354] Suitable reducing agents include, but are not limited to,hydrogen over palladium or platinum on carbon, borane or complexes ofborane, e.g., borane-pyridine, borane-t-butylamine, andborane-dimethylamine complex; and borohydride reducing agents such assodium borohydride or sodium cyanoborohydride. Sodium cyanoborohydrideis a preferred reducing agent.

[0355] Compounds of formula I(r) may be prepared from compounds offormula I(n) as illustrated below where p, n, R³, R⁷, and R¹⁰ are asdescribed supra.

[0356] The compounds of formula I(n) may be converted to compounds offormula I(r). Such reactions are well known transformations, see, e.g.,Larock, “Comprehensive Organic Transformations”, pg. 421, VCHPublishers, New York, N.Y., 1989, hereafter referred to as “Larock”.

[0357] The compound of formula I(n) may be may be reduced to thecorresponding alcohol, activated (i.e. mesylation), reacted with anappropriate azide, reduced, and then acylated. Additionally, the Curtiusrearrangement may be employed to give the compound of formula I(r). Seethe preparation/Example section for specifics.

[0358] The Curtius rearrangement is performed by converting theactivated compound, in an appropriate solvent, with an appropriateazide, then an appropriate alcohol, to provide a compound of formulaI(r). As the skilled artisan would appreciate, the activated compound,dissolved in an appropriate solvent, is first treated with anappropriate azide and optionally a catalyst to provide the intermediate.The intermediate is treated with an appropriate alcohol to obtain thecompound of formula I(r). Once the reaction is complete, as measured bythe consumption of the substrate, the resulting compound of formula I(r)may be isolated by standard extractions and filtrations. If desired, theresulting compound of formula I(r) may be further purified bychromatography or crystallization as appropriate.

[0359] Appropriate solvents must be capable of dissolving a sufficientamount of the activated compound and the azide for the reaction toproceed. Useful organic solvents include hexamethylphosphoramide,dimethylformamide, and preferably toluene.

[0360] The skilled artisan would appreciate that the Curtiusrearrangement may be preformed via a number of azides and that reactionconditions may vary depending upon the azide used. For example if sodiumazide, potassium azide, and the like are used the compound must first beconverted to the activated acid with an appropriate activating agent,such as ethyl chloroformate or sulfuric acid. The substrate may need tobe pretreated with the activating agent, such as the case with ethylchloroformate, or may need to be added simultaneously. The skilledartisan would appreciate the potential for reaction at an ester site ofthe substrate, if the molecule is treated with the azide first as is thecase in these circumstances.

[0361] Preferably, diphenylphosphoryl azide is used in the process ofthe present invention without an activating agent.

[0362] Appropriate alcohols are lower alkyl alcohols such as methanol,ethanol, propanol, isopropanol, butanol, benzyl, t-butanol, TMS-ethanol,and the like.

[0363] The reaction may be carried out over a large range ofconcentrations, from about 0.001 molar to about 2.0 molar of the azide,dependent upon the solubility of the particular azide in the chosensolvent. The reaction may also be performed on slurries of the azide solong as a sufficient amount of the azide is soluble in the solvent forthe reaction to proceed. Preferably the process is performed at aconcentration from about 0.1 molar to about 1.0 molar. A concentrationof about 0.3 to about 0.4 molar is most preferred.

[0364] Reactions may be performed between about 80° C. and about 130°C., preferably between about 100° C. and about 120° C. Most preferablythe reactants are combined at temperature of about 20° C. to about 30°C., then heated to about 80° C. and about 120° C., the azide is thenadded, and the reactants are stirred for about 0.5 to about 1.5 hours atreflux. An appropriate alcohol is then added and heated to about 70° C.to about 90° C. for about 3 to about 24 hours, preferably from about 75°C. to about 85° C. for about 8 to about 12 hours.

[0365] Compounds of formula I where Y is C(R¹¹)(R¹¹)NR⁴R⁵ or OR², R² is(CH₂)₂NR⁴R⁵, and R⁵ is C₁-C₆ alkyl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle, or COR⁷,may be prepared from compounds of formula I(f) and I(h) as illustratedin Scheme 6 below where X is halide and het, n, p, R¹¹, R⁴, R¹⁰, and R¹²are as described supra.

[0366] The compounds of formulas I(f) and 1(h) may be reductivelyalkylated to form the corresponding compounds of formulas I(g) and I(i),respectively. Reductive alkylation of primary amines are well knowntransformations, see, e.g., Larock, pg. 434435.

[0367] Once it is determined that the compound of formula IV has beensubstantially consumed, the intermediate is typically reacted in situwith a suitable reducing agent to provide the compounds of formula I(g)and I(i), respectively. The overall conversion may be performed at about0° C. to the boiling point of the mixture but room temperature is apreferred reaction temperature. The formation of the compounds offormulas I(g) and I(i) may take from 15 minutes to 24 hours as measuredby the consumption of the substrate.

[0368] A base is typically employed when the compound of formula I(f) orI(h) is an acid addition salt in order to convert the salt to its freeamine form. Preferred bases for this purpose are N-methylmorpholine andtriethylamine. A preferred Lewis acid catalyst is titanium(IV)isopropoxide. Suitable reducing agents include, but are not limited to,borane or complexes of borane, e.g., borane-pyridine,borane-t-butylamine, and borane-dimethylamine complex; and lithiumaluminum hydride.

[0369] Compounds of formulas I(f) and I(h) may be converted to othercompounds of the invention by methods well known in the chemical arts.Additional compounds of formula I may be prepared as follows, where Y is-E-NR⁴R⁵ or -E-OR², R² is (CH₂)₂NR⁴R⁵, R⁵ is COR⁷, and R⁷ is NR⁴R^(6′)or R⁵ is a moiety of the formula

[0370] R³⁰ is R^(6′) or R⁸; and het, n, p, A, R⁴, R^(6′), R⁸, R¹⁰, andR¹¹ are as described supra.

[0371] The primary amines of formulas I(h) and I(f) may be reacted, bymethods well known in the art, with the isocyanates or isothiocyantes offormula VII to prepare the corresponding ureas and thioureas of formulasI(k) and I(o), see, generally, March, pages 802-803.

[0372] Compounds of formula I where Y is C(R¹¹)(R¹¹)NR⁴R⁵, and R⁵ isSO₂R⁸ can be prepared as described in Scheme 8, wherein het, n, p, A,R¹¹, R⁴, R⁸, and R¹⁰ are as described supra.

[0373] Compounds of formula I(f) may be converted to other compounds ofthe invention via standard combinatorial synthetic techniques. Forexample, a compound of formula I(f) dissolved or suspended in a suitablesolvent, optionally in the presence of a base, may be treated with acompound of formula VI to provide a compound of formula I(o) where R⁵ isSO₂R⁸. Typically a preferred and convenient solvent is dichloromethane.When a base is employed, triethylamine is typically preferred.Furthermore, when a base is employed, the base and compound of formulaVI are typically employed in a slight stoichiometric excess. For examplea 1.01 to 1.40 molar excess, relative to the compound of formula I(f),is generally employed. About 1.15 to about 1.25 fold molar excess istypically preferred. When a base is not employed, the compound offormula VI is typically employed in a relatively larger stoichiometricexcess. For example, about a 1.5 to about a 3 molar excess, relative tothe compound of formula I(f), is usually employed. About 1.8 to about2.2 fold molar excess is typically preferred. The reaction is usuallyperformed at a temperature range of about 0° C. to about the refluxtemperature of the solvent for from 10 minutes to 18 hours. Preferably,the reaction is performed at about 15° C. to about 40° C. for from 5minutes to about 1 hour.

[0374] Compounds of formula I where Y is C(O)R³ and R³ is OR¹³ or NR⁴R⁶may be prepared from compounds of formula I(l) as illustrated in Scheme9 below wherein R³¹ is NR⁴R⁶ or OR¹³; and het, n, p, A, R⁴, R⁶, and R¹³are as described supra

[0375] Compounds of formula I(l), prepared as described in Scheme 1, mayalso be converted to other compounds of the invention via solution orsolid phase synthetic techniques. For example, acids of formula I(l) maybe treated with activating agents to form the activated carboxylic acidderivatives of formula I(l) by methods well known in the chemical arts.See, e.g., The Peptides, Peptide Synthesis and the Examples andPreparations sections below.

[0376] Generally, preparation of compounds of formula I(m) where R³¹ isNR⁴R⁶ is performed in a manner similar to the reaction of compounds offormula I(f) or I(h) described in Scheme 6. Specifically, such compoundsof formula I(m) may be prepared by dissolving or suspending a compoundof the activated carboxylic acid derivatives of formula I(l) in asuitable solvent, optionally in the presence of a suitable base, andadding an amine of formula III. Typically a preferred and convenientsolvent is dichloromethane. Preferred bases are triethylamine andpiperidinylmethylpolystyrene resin. The amine is typically employed in amolar excess. For example, about a 1.5 to about a 3 molar excess,relative to the compound of the activated carboxylic acid derivatives offormula I(l) is usually employed. About 1.8 to about 2.2 fold molarexcess is typically preferred. The reaction is usually performed in atemperature range of about 0° C. to about the reflux temperature of thesolvent for from 10 minutes to 18 hours. Preferably, the reaction isperformed at about 15° C. to about 40° C. for from 5 minutes to about2.5 hours.

[0377] The compounds of formula I(m) where R³¹ is OR¹³ may be preparedby methods well known in the chemical arts. For instruction on theconversion of activated carboxylic acid derivatives to esters see, e.g.,Larock at 978-979. Alternatively, these compounds of formula I(m) may beprepared directly from the acids of formula I(l) as taught in the Larockreference at pages 966-972.

[0378] The starting materials and compounds of the present invention maybe obtained by a number of routes. For example, compounds of formula Umay be prepared according to the routes shown in Schemes 8 and 9.

[0379] Where het, n, p, Y, A, and R¹⁰ are as described supra, compoundsof formula II may be prepared according to Scheme 10.

[0380] Compounds of formula XI may be converted to the correspondingacid halide by methods well known to one skilled in the art. Compoundsof formula H may be prepared by dissolving or suspending an acid halideof a compound of formula XI in a suitable solvent and adding a compoundof formula XII in a suitable solvent. Triethylamine or dimethylformamideis a convenient solvent and is typically preferred for the compound offormula XI. A 1:1 mixture of DMF and dichloromethane is a convenientsolvent and is typically preferred for the amine of formula XII. Thisamide forming reaction is also preferably run in the presence of4-dimethylaminopyridine (DMAP).

[0381] For compounds in which het is pyrazole, the addition of1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) tothe reaction is preferred. The compound of formula XI is preferably thecorresponding carboxylic acid and is employed in an equimolar amount,relative to the compound of formula XII, but a slight excess (about a0.05 to about 0.15 molar excess) is acceptable. DMAP is employed in acatalytic fashion. For example, about 5 molar percent to about 15 molarpercent, relative to the compound of formula XII, is typically employed.A 10 molar percent is usually preferred.

[0382] Compounds of formula XII where Y is —E-C(O)R³, -E-NR⁴Pg, or-E-O(CH₂)₂NR⁴-Pg, which are used to prepare compounds of formula I(l),I(n), I(f), and I(h) are well known in the art and to the extent notcommercially available, are readily synthesized by standard procedurescommonly employed in the art.

[0383] Compounds of formula XII(a) where Y is -E-NR⁴R⁵ and p, n, A, E,R⁴, and R⁵ are as described supra can be prepared as illustrated inScheme 11 from compounds of formula (i) wherein Y is -E-C(O)R³ and R³ ishydrogen.

[0384] Compounds of formula XII(a) may be prepared from compounds offormula (i) in a manner similar to that as taught in the Larockreference at pages 421-430. For an example of this transformation, seePreparation 124. Compounds of formula (i) are well known in the art andto the extent not commercially available, are readily synthesized bystandard procedures commonly employed in the art.

[0385] Compounds of formula XI(c), XII(d), and XII(e) where Y is-E-S(O)_(q)R³, and R³, p, A, and E are as described supra can beprepared as illustrated in Scheme 12.

[0386] Compounds of formula XII(c) may prepared from compounds offormula (Iv) by methods well known to the skilled artisan. One manner isto combine the compound of formula (Iv) with sodium hydride in anappropriate solvent, preferably dimethylformamide, and combining withthe appropriate thiol. The compound of formula XII(c) may be furtheroxidized to form the compounds of formulas XII(d) and XII(e) in a mannersimilar to that as taught in Preparation 175 and Examples 368, and467468. Compounds of formula (iii) can be converted to compounds offormula (Iv) in a manner similar to that of Preparation 169. Compoundsof formula (iii) are well known in the art and to the extent notcommercially available, are readily synthesized by standard procedurescommonly employed in the art.

[0387] Furthermore, the transformations described in Schemes 3-8 may beperformed before the cyclization described in Scheme 1 and 2 to providethe compounds of formula XI with a fully elaborated R substituent.Additionally, the skilled artisan would appreciate that thetransformations of Schemes 11-13 may be performed after the cyclizationdescribed in Schemes 1 and 2.

[0388] Additionally, compounds of formula XII may be prepared accordingto the following routes where, unless otherwise provided, R^(b) is thesubstituent from the carbon atom of het, R^(a) is the substituent fromthe saturated nitrogen of het, the second heteroatom is an oxygen orsulfur, and other variables are as described supra.

[0389] Compounds of formula XI(a), where het is [4,3-c]isoxazole, may beprepared in a manner similar to that described in the literature, forexample, see Chen Y P, et al, Heterocycles, 1995, 41, 175, andChantegrel B, et. al, J. Org. Chem, 1984, 49, 4419-4424.

[0390] Compounds of formula XVI may be prepared by dissolving orsuspending a compound of formula XV and a suitable base in a suitablesolvent and adding a compound of formula XIV in a suitable solvent,dropwise. Toluene is a convenient solvent and is typically preferred.Triethylamine is the preferred base. The compound of formula XIV istypically and preferably employed in an equimolar amount, relative tothe compound of formula XV, but a slight excess is acceptable.

[0391] The reactants are preferably combined at about 0° C. and theresulting solution is typically warmed to room temperature and mixed forfrom about 18 hours to about 24 hours.

[0392] The compound of formula XVI may then be converted to the compoundof formula XIII by dissolving or suspending a compound of formula XVI ina suitable acidic solvent and adding hydroxylamine hydrochloride.Glacial acetic acid is a convenient acidic solvent and is typicallypreferred. The ester group is then hydrolyzed to the correspondingcarboxylic acid of formula XI(a) through standard procedures commonlyemployed in the art, see for example, Larock, pgs 981-985.

[0393] The reactants are preferably combined at about room temperaturethen heated to reflux for from about 30 minutes to about 60 minutes.Preferably the reaction is heated to reflux from about 40 to 45 minutes.

[0394] Compounds of formula XIV and XV are known in the art and, to theextent not commercially available, are readily synthesized by standardprocedures commonly employed in the art.

[0395] Compounds of formula XI(b) and (c), wherein het is[4,5-c]isoxazole, may be prepared according to route 2.

[0396] Generically, the compound of formula XVIII and hydroxylaminehydrochloride are suspended or dissolved in a suitable solvent and asuitable base is added. After the reaction is complete, the solution isacidified with a suitable acid and the resulting oxime is purified byknown methods. Typically a preferred and convenient solvent iswater/methanol. Typically a preferred and convenient base is sodiumhydroxide.

[0397] The reactants are preferably combined at about 0° C. and theresulting solution is typically mixed for about 1 hour at about 25-30°C., until the reaction is complete. After the reaction is complete, thesolution is acidified with a suitable acid, preferably hydrochloricacid, and the resulting oxime is purified by known methods.

[0398] The purified oxime is dissolved or suspended in a suitablesolvent, preferably DMF, and is then reacted with N-chlorosuccinimide(NCS). Preferably, NCS is added in small portions to control theexpected exotherm. The initial NCS addition results in a slighttemperature decrease. If the reaction does not self-initiate withinabout 10 minutes, as indicated by a slight temperature rise, hydrogenchloride may be bubbled into the DMF solution. If the reaction does notbegin within about 10 to 15 minutes, heating the solution to about45-60° C. is desirable. Once the reaction begins, the temperature ispreferably maintained below about 35° C. for benzaldoximes withelectron-donating substituents and below about 50° C. for strongelectron-withdrawing substituents. Completion of the reaction isindicated by cessation of the exotherm.

[0399] The compound of formula XIX is then converted to the compound offormula XX by methods well known to the skilled artisan. The compound offormula XIX and an appropriate methyl-2-butynoate are dissolved orsuspended in a suitable solvent, preferably ethyl ether, and Et₃N isadded. The reactants are combined at about room temperature and mixedfrom about 12 to 24 hours, until the reaction is complete.

[0400] The ester group of the compounds of formula XX is then hydrolyzedto the corresponding carboxylic acid of formula III(b) through standardprocedures commonly employed in the art, see for example, Larock, pgs981-985.

[0401] Compounds of formula XX may be prepared in a manner similar tothat described in the literature, for example, see Liu K, Shelton B R,Howe, R K, J. Org. Chef, 1980, 45, 391-3918.

[0402] Compounds of formula XXI may be prepared in a manner similar tothat described in the literature, for example, see Stevens R L, AlbizatiK F, Tetrahedron Lett. 1984, 25, 4587. For an example of thistransformation, see Preparation 3.

[0403] Compounds of formula XI(c) may be prepared from compounds offormula XX in a manner similar to that described in the literature, forexample, see Micetich R G, Chin C G, Can. J. Chem. 1970, 48, 1371. Foran example of this transformation, see Preparation 4.

[0404] Compounds of formula XVIII are known in the art and, to theextent not commercially available, are readily synthesized by standardprocedures commonly employed in the art.

[0405] The isoxazole compounds of formula XI may be converted to theisothiazole by methods well known in the art, for example see McGregor DN, Corbin U, Swigor J E, and Cheney L C, “Synthesis of isothiazoles: Thetransformation of isoxazoles into isothiazoles,” Tetrahedron, 1969, 25,389-395.

[0406] Compounds of formula XI(d) where het is pyrazolyl may be preparedas illustrated below.

[0407] Compounds of formula XXIII may be prepared by combining thecompound of formula XXII with ethyl trifluoroacetyl vinyl ether in amanner similar to that described in the literature, for example, seeKamitori et al, J. Het. Chem., 1993, 30, 389. For examples of thistransformation, see Preparations 7-8.

[0408] Additionally, compounds of formula XXII may be prepared fromaldehyde hydrazones and ethyl propiolate as is further described byKamitori et al, Heterocycles, 1994, 38, 21.

[0409] The tifluoromethyl ketone of formula XXII may be converted to thecorresponding carboxylic acid of formula XI(d) in a manner similar tothat described in the literature, for example, see Delgado A, Clardy J,Tetrahedron Lett. 1992, 33, 2789-2790.

[0410] Compounds of formula XXII are known in the art and, to the extentnot commercially available, are readily synthesized by standardprocedures commonly employed in the art.

[0411] Compounds of the invention where het is oxazolyl or imidazolylmay be prepared as illustrated below.

[0412] Compounds of formula XI(e) may be prepared in a manner similar tothat described in the literature, for example, see Nunami et al, J. Org.Chem. 1994, 59, 7635-7642.

[0413] The compound of formula XXV is converted to the compound offormula XXVIII by methods well known to the skilled artisan. Thecompound of formula XXV is dissolved or suspended in a suitable solvent,preferably tetrahydrofuran, and a base is added, preferably Et₃N. Thereactants are combined at about room temperature, preferably under aninert atmosphere, and mixed from about 30 minutes to 2 hours, until thereaction is complete.

[0414] The ester group of the compounds of formula XXVIII is thenhydrolyzed to the corresponding carboxylic acid formula XI(f) throughstandard procedures commonly employed in the art, see for example,Larock, pgs 981-985.

[0415] Compounds of formula XIV and XXIV are known in the art and, tothe extent not commercially available, are readily synthesized bystandard procedures commonly employed in the art.

[0416] Compounds of the invention where het is imidazolyl may,additionally, be prepared as illustrated below:

[0417] The compound of formula XI(e)′ may be prepared by methods wellknown in the art. For specific conditions, see the preparation section(preparations 400-405).

[0418] The pharmaceutical salts of the invention are typically formed byreacting a compound of formula I with an equimolar or excess amount ofacid or base. The reactants are generally combined in a mutual solventsuch as diethylether, tetrahydrofuran, methanol, ethanol, isopropanol,benzene, and the like for acid addition salts, or water, an alcohol or achlorinated solvent such as dichloromethane for base addition salts. Thesalts normally precipitate out of solution within about one hour toabout ten days and can be isolated by filtration or other conventionalmethods.

[0419] Acids commonly employed to form pharmaceutical acid additionsalts are inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, spheric acid, phosphoric acid, and the like, andorganic acids such as p-toluenesulfonic, methanesulfonic acid,ethanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonicacid, succinic acid, citric acid, tartaric acid, benzoic acid, aceticacid, and the like. Preferred pharmaceutical acid addition salts arethose formed with mineral acids such as hydrochloric acid, hydrobromicacid, and sulfuric acid, and those formed with organic acids such asmaleic acid, tartaric acid, and methanesulfonic acid.

[0420] Bases commonly employed to form pharmaceutical base additionsalts are inorganic bases, such as ammonium or alkali or alkaline earthmetal hydroxides, carbonates, bicarbonates, and the like. Such basesuseful in preparing the salts of this invention thus include sodiumhydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate,sodium carbonate, sodium bicarbonate, potassium bicarbonate, calciumhydroxide, calcium carbonate, and the like. The potassium and sodiumsalt forms are particularly preferred.

[0421] It should be recognized that the particular counterion forming apart of any salt of this invention is not of a critical nature, so longas the salt as a whole is pharmacologically acceptable and as long asthe counterion does not contribute undesired qualities to the salt as awhole.

[0422] The optimal time for performing the reactions of Schemes 1-8 andRoutes 1-5 can be determined by monitoring the progress of the reactionvia conventional chromatographic techniques. Furthermore, it ispreferred to conduct the reactions of the invention under an inertatmosphere, such as, for example, argon, or, particularly, nitrogen.Choice of solvent is generally not critical so long as the solventemployed is inert to the ongoing reaction and sufficiently solubilizesthe reactants to effect the desired reaction. The compounds arepreferably isolated and purified before their use in subsequentreactions. Some compounds may crystallize out of the reaction solutionduring their formation and then collected by filtration, or the reactionsolvent may be removed by extraction, evaporation, or decantation. Theintermediates and final products of formula I may be further purified,if desired by common techniques such as recrystallization orchromatography over solid supports such as silica gel or alumina Theskilled artisan will appreciate that not all substituents are compatiblewith all reaction conditions. These compounds may be protected ormodified at a convenient point in the synthesis by methods well known inthe art.

Preparation 1 2-((1R,3R)-3-Hydroxycyclohexyl)malonic acid dibenzyl ester

[0423] To a −78° C. solution of 2-(1(R)-3-oxo-cyclohexyl)malonic aciddibenzyl ester (see Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.;Shibasaki, M. Chem. Eur. J. 1996, 2, 1368-1372.) (3.80 g, 10.0 mmol) inTHF (50 mL) under N₂ was added L-selectride (11.0 mL at 1.0 M, 11.0mmol) dropwise and the mixture was stirred for 2 h at −78° C. EtOAc (100mL) and H₂O (100 mL) were added and the mixture was warmed to roomtemperature. Dilution with more EtOAc followed by washing with 1N NaOH,saturated NH₄Cl, brine, drying (MgSO₄), and column chromatography(silica gel, hexanes:EtOAc gradient) gave title compound (2.92 g, 76%).Mass spectrum (ES−)(m/z) 381.2 [M−1].

Preparation 2 (1R,3R)-(3-Hydroxycyclohexyl)acetic acid benzyl ester

[0424] A solution of a compound from preparation 1 (2.30 g, 6.02 mmol),LiCl (0.511 g, 12.0 mmol), H₂O (0.217 mL, 12.0 mmol), and DMSO (20 mL)was lowered into a 165° C. oil bath for 2 h. The reaction was cooled toroom temperature and diluted with EtOAc. Washing with H₂O and brine,drying (MgSO₄), and column chromatography (silica gel, hexanes: EtOAcgradient) gave title compound (1.12 g, 75%).

[0425]¹H NMR (CDCl₃, 400 MHz) δ 7.34-7.25 (m, 51, 5.06 (s, 2H), 4.02 (m,1H), 2.21 (m, 2H), 1.71-1.59 (m 4H), 1.50-1.40 (m, 4H), 1.30 (m, 1H),1.00 (m, 1H) ppm.

Preparation 3 (1R,3S)-(3-Azidocyclohexyl)acetic acid benzyl ester

[0426] To a solution of a compound from preparation 2 (1.05 g, 4.24mmol), triphenylphosphine (1.33 g, 5.07 mmol), and hydrazoic acid (6.4mL, at 1.0 M, 6.4 mmol) in toluene (7 mL) was added DEAD (1.0 mL, 6.4mmol) dropwise and stirred for 20 min. The mixture was diluted withEtOAc, washed with 0.1N NaOH, H₂O, and brine, dried (MgSO₄), andchromatographed (silica gel, hexanes: EtOAc gradient) to give the titlecompound (0.916 g, 80%).

Preparation 42-((1R,3S)-3-Azidocyclohexyl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0427] A solution of a compound from preparation 3 (215 mg, 0.788 mmol)and NaOH (0.32 mL at 5M, 1.6 mmol) in MeOH (5 mL) was heated at 50-55°C. for 3 h then cooled to room temperature. The reaction was dilutedwith H₂O and acidified with aqueous HCl to pH 2. Extraction with EtOAcand subsequent washing (brine) and drying (Na₂SO₄) gave the crudecarboxylic acid. A mixture of the crude acid, 3,4,5-trimethoxyaniline(288 mg, 1.58 mmol), EDCI (262 mg, 1.58 mmol), DMAP (20 mg, 0.16 mmol)in CH₂Cl₂ (5 mL) was stirred for 17 h. The mixture was diluted withCH₂Cl₂ and extracted with 1N HCl and brine then dried (MgSO₄). Columnchromatography (silica gel, hexanes: EtOAc gradient) gave the titlecompound (255 mg, 93%). Mass spectrum (ES+) (m/z) 349.2 [M+1]. MS (ES+):[M+1] 349.2 m/z.

Preparation 52-((3S,1R)-3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)-N-3,4,5-trirhethoxyphenyl)acetamide

[0428] A mixture of a compound from preparation 4 (250 mg, 0.72 mmol),10% palladium on carbon (76 mg, 0.07 mmol), and EtOH (5 mL) was stirredunder an atmosphere of hydrogen (balloon). After 2 h the reaction wasfiltered through a pad of celite with the aid of MeOH and concentrated.Benzene was added to the resulting residue followed by concentration.The residue was dissolved in CH₂Cl₂ (5 mL) followed by addition of3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (236mg, 0.87 mmol) and DMAP (175 mg, 1.44 mmol) and stirred for 16 h. Themixture was applied to a silica gel column and elution (hexanes: EtOAcgradient) gave the title compound (256 mg, 64%). Mass spectrum (ES+)(m/z) 560.2 [M+1].

Preparation 6 N-(3,4,5-Trimethoxyphenyl)-2-(3-oxocyclopentyl)acetamide

[0429] To a solution of 1.0 g (7 mmol) of 3-oxocyclopentyl acetic acidin dichloromethane (18 mL) and DMF (1 mL), was added 0.68 mL (7.7 mmol)oxalyl chloride. After 30 min, the solvent was removed in vacuo. Theresidue was dissolved in dichloromethane (20 mL), cooled to 0-5° C., and1.29 g of 3,4,5-trimethoxyaniline (0.63 mmol) was added followed by 0.68mL of pyridine (8.4 mmol). After 15 min, the reaction was allowed towarm to ambient temperature. After 2 h, the reaction was rinsed with 1NHCl, followed by aq. sodium bicarbonate, and water (3×). The organiclayer was dried, the solvent removed in vacuo and the residuechromatographed on a silica gel with 2% methanol in methylene chlorideto yield 0.25 g of the title compound. MS(ES+)m/z=308.

Preparation 7 N-(3,4,5-Trimethoxyphenyl)-23-hydroxycyclopentyl)acetamide

[0430] A solution of 1.07 g (3.5 mmol) of a compound from preparation 6and 0.136 g of sodium borohydride (3.5 mmol) in methanol (60 mL) wasstirred 12 h. The solvent was removed in vacuo, the residue dissolved inethyl acetate and rinsed with 1N HCl followed by water. The organiclayer was dried and concentrated in vacuo. The residue waschromatographed on silica gel and eluted with 5% methanol indichloromethane to yield 0.45 g of the title compound. MS(FS+)m/z=310.Cis/trans racemic

Preparation 8N-(3,4,5-Trimethoxyphenyl)₂-(3-methylsulfonyloxycyclopentyl)acetamide

[0431] A solution of 0.45 g (1.46 mmol) of a compound from preparation 7and 0.135 mL (1.75 mmol) of methanesulfonyl chloride and 0.27 mL (1.9mmol) of triethylamine in dichloromethane (15 mL) was stirred 2 h. Thesolvent was removed in vacuo and replaced with ethyl acetate. Theorganic layer was rinsed with 1N HCl followed by aq. sodium bicarbonate,then brine and dried to yield 0.115 g of the title compound.MS(ES+)m/z=387.9.

Preparation 9 N-(3,4,5-Trimethoxyphenyl)-2-(3-azidocyclopentyl)acetamide

[0432] A solution of 0.6 g (1.55 mmol) of a compound from preparation 8,and 0.21 g (4.3 mmol) of lithium azide in DMF (12 mL) was stirred 12 h.Water and ice were added to the reaction, and the mixture was extractedwith ethyl acetate. The organic layer was washed 5 times with water,dried, concentrated in vacuo, and the residue was chromatographed onsilica gel and eluted with hexane/ethyl acetate 3:2 to yield 0.13 g ofcis and 0.21 g of trains of the title compound. MS(ES+) m/z=335.

Preparation 10cis-N-(3,4,5-Trimethoxyphenyl)₂-(3-aminocyclopentyl)acetamide

[0433] To a solution of 0.13 g (0.39 mmol) of a cis compound frompreparation 9 in ethyl acetate (30 mL) was added 0.026 g of 10%palladium on carbon and the mixture was hydrogenated at 50 psi over 1.5h. The catalyst was removed by filtration over celite and the solventwas removed in vacuo to yield 0.128 g of the title compound MS(ES+)m/z=309. Cis (racemic)

Preparation 11trans-N-(3,4,5-trimethoxyphenyl)-2-(3-aminocyclopentyl)acetamide

[0434] In the same manner as the preparation 10, 0.21 g of a tanscompound from preparation 9 was converted to 0.20 g of the titlecompound. MS(ES+)m/z=309. Trans (racemic)

Preparation 122-(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclopentyl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0435] A solution of 0.123 g (0.42 mmol) of a compound from preparation10, 0.03 g (0.46 mmol) of3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride, and0.07 mL (0.5 mmol) of triethylamine in dichloromethane (10 mL) wasstirred for 12 h. The solvent was removed in vacuo and replaced withethyl acetate. The organic layer was washed with 1N HCl, then aq.NaHCO₃, followed by brine and dried. The solvent was removed in vacuo toyield 0.255 g of the title compound. MS(ES+) m/z=545.8. cis (racemic)

Preparation 132-(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclopentyl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0436] In the same manner as preparation 12, 0.2 g (0.65 mmol) of acompound from preparation 11 was converted to 0.324 g of the titlecompound. MS(ES+)m/z=545.8. Racemic

Preparation 14 N-((1S,3R)-3-Cyanomethylcyclopentyl)(t-butoxy)carboxamide

[0437] To a solution of 8.2 g (0.0222 mol) ofN-[t-butoxycarbonyl]-2-(p-toluenesulfonyloxymethyl)cyclopentylamine inDMF (250 mL) was added 3.3 g (0.067 mmol) of NaCN and the suspension washeated at 80° C. for 4 h. The solvent was removed in vacuo at 40° C. andthe residue was slurried in brine. The aqueous layer was extracted withethyl acetate, dried and the solvent was removed in vacuo to yield 5.7 gof the title compound. MS (ES+)m/z=225. (one enantiomer)

Preparation 15 2-{(3S,1R)-3-[(t-Butoxy)carbonylamino]cyclopentyl}aceticacid

[0438] A suspension of 2.0 g (8.9 mmol) of a compound from preparation14 in 3N KOH (32 mL) and EtOH (12 mL) was heated at reflux for 6 h(solution). The alcohol was removed in vacuo and the reaction was cooledand neutralized with 3N HCl. The product was separated by filtration,rinsed with water and dried in vacuo at 40° C. to yield 1.33 g of thetitle compound. MS(ES+)m/z=244.

Preparation 162-{(3S,1R)-3-[(t-Butoxy)carbonylaminolcyclopentyl-N-(3,4,5-trimethoxyphenyl)acetamide

[0439] To a solution of 0.1 g (0.4 mmol) of a compound from preparation15 in THF/DMF 1:1 (5 mL) was added 0.061 g (0.44 mmol) of1-hydroxy-7-azabenzotriazole and 0.086 g (0.44 mmol) of EDCI. After 40nm, 0.083 g (0.44 mmol) of 3,4,5-trimethoxyaniline was added. After 3.25h, the solvent was removed in vacuo and replaced with ethyl acetate. Theorganic layer was rinsed with 1N HCl, aq. NaHCO₃, then 3× with water.The organic layer was dried and the solvent was removed in vacuo toyield 0.144 g of the title compound. MS(ES+)m/z=409.

Preparation 172-((3S,1R)-3-Aminocyclopentyl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0440] A solution of 0.48 g (0.362 mmol) of a compound from preparation16 in TFA (10 mL) was stirred for 1 h, after which the TFA was removedin vacuo and replaced with ethyl acetate. The organic layer was rinsedwith 1N NaOH followed by brine and dried. The organic layer was removedin vacuo to yield 0.3 g of the title compound. MS(ES+)m/z=309.

Preparation 182-((3S,1R)-3-([3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclopentyl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0441] In the same manner as preparation 12, 0.32 g (1.04 mmol) of acompound from preparation 17 yielded 0.52 g of the title compound.MS(ES+)m/z=546.

Preparation 19 N-(t-Butoxycarbonyl)-3-aza-2-oxabicyclo[3.2.1]nonane

[0442] A solution of 0.59 g (4.8 mmols) of2-oxo-3-azabicyclo-[3.2.1]nonane, 2.07 g (9.6 mmol) of (BOC)₂O and 1.173g (9.6 mmol) of DMAP in CH₂Cl₂ (15 mL) was stirred 12 h. The solvent wasremoved in vacuo and replaced with ethyl acetate. The organic layer wasrinsed with 1N HCl followed by brine, dried and the solvent removed invacuo to yield 0.495 g of the title compound. MS(ES+)m/z=225.9

Preparation 20cis-3-{[(t-Butoxy)carbonylamino]methyl}cyclopentanecarboxylic acid

[0443] To a solution of 2.22 g (0.98 mmol) of a compound frompreparation 19 in THF (113 mL) was added H₂O (32 mL) and the solutioncooled to 5° C. Water (30%, 11.95 mL, 9.8 mmol) was added followed by2.08 g (4.9 mmol) of LiOH and the reaction was allowed to warm toambient temperature. After 2 h, the reaction was quenched with sodiumsulfite solution (10%) and the THF was removed in vacuo. With cooling,the reaction was acidified with 6N HCl and extracted with ethyl acetate,dried and the solvent removed in vacuo to yield 1.583 g of the titlecompound. MS(ES+)m/z=243.9.

Preparation 21cis-N-(3-{[(t-Butoxy)carbonylamino]methyl}cyclopentyl)(phenylmethoxy)carboxamide

[0444] To warm solution of 0.244 g (1.0 mmol) of a compound frompreparation 20 in toluene (8 mL) was added 0.2 mL (1.4 mmol) of Et₃Nfollowed by 0.3 mL (1.4 mmol) of diphenylphosphoryl azide. The reactionwas stirred at ambient temperature for 2.5 h and refluxed for 1.5 h. Thesolvent was removed in vacuo and replaced with ethyl acetate which wasrinsed with aq. NaHCO₃, aq. KHSO₄ and brine. The solvent was removed invacuo and the residue was chromatographed on silica gel with 0.5-1%MeOH/CH₂Cl₂ to yield 0.264 g of the title compound. MS(ES+)m/z=349.

Preparation 22 cis-N-[(3-Aminocyclopentyl)methyl](t-butoxy)carboxamide

[0445] A suspension of 0.264 g (0.76 mmol) of a compound frompreparation 21 and 0.034 g of Pd/C 10% in MeOH (40 mL) was reduced at1.0 atm. of H₂ over 2.5 h. The catalyst was removed by filtration andthe solvent was removed in vacuo to yield 0.187 g of the title compound.MS(ES+)m/z=215.

Preparation 23cis-N-[(3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclopentyl)methyl](t-butoxy)carboxamide

[0446] To a suspension of 0.187 g (0.873 mmol) of a compound frompreparation 22 in dichloromethane (10 mL) was added 0.263 g (0.96 mmol)of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloridefollowed by 0.2 mL (1.4 mmol) of Et₃N. After 70 min, the solvent wasremoved in vacuo and replaced with ethyl acetate. The organic layer wasrinsed with 1N HCl followed by aq. NaHCO₃, dried and the solvent wasremoved in vacuo to give a residue which was chromatographed on silicagel with hexane/ethyl acetate 3-1 to yield 0.156 g of the titlecompound. MS(ES+)m/z=452.

Preparation 24cis-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclopentyl]methyl)}(t-butoxy)carboxamide

[0447] To a solution of 0.136 g (0.3 mmol) of a compound frompreparation 23 in DMF (7.0 mL) at 0-5° C. was added 0.6 mL (0.3 mmol) ofKHMDS (0.5N in THF). After 2 min, cooling was removed. After 3additional min, 1N HCl was added and the mixture was extracted withethyl acetate. The organic layer was rinsed with water, dried andconcentrated to a foam in vacuo which was chromatographed on silica gelwith hexane/ethyl acetate 3:1 to yield 0.057 g of the title compound.MS(ES+)m/z=432.

Preparation 25 2-(3-Aminocyclopentyl)ethanenitrile

[0448] In the same manner as preparation 17, 0.3 g (4.5 mmol) of acompound from preparation 14 was deprotected with TFA to yield 0.087 gof the title compound MS(ES+)m/z=125.

Preparation 26N-[(1R,3S)-3-(cyanomethyl)cyclopentyl][3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

[0449] In the same manner as preparation 18, 0.08 g (0.65 mmol) of acompound from preparation 26 was acylated with3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride toyield a residue which after chromatography on silica gel withhexane/ethyl acetate 1:1 yielded 0.177 g of the title compound.MS(ES+)m/z=362.

Preparation 272-[(3S,1R)₃-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclopentyl]ethanenitrile

[0450] In the same manner as preparation 24, 0.166 g (0.46 mmol) of acompound from preparation 27 was cyclized to a residue which uponchromatography on silica gel with hexane/ethyl acetate 2:1 yielded 0.099g of the title compound. MS(ES+)m/z=342.

Preparation 282-[(3S,1R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclopentyl]aceticacid

[0451] A suspension of 0.086 g (0.25 mmol) of a compound frompreparation 27 in HCl conc. (40 mL) was refluxed for 6 h, after whichthe reaction was concentrated to a residue in vacuo at 40° C. Theresidue was taken into diethyl ether, the insolubles filtered anddiscarded, and the filtrate was extracted with 1N NaOH. The basic layerwas acidified with 1N HCl, extracted with ethyl acetate, dried andconcentrated in vacuo to yield 0.059 g of the title compound.MS(ES+)m/z=361.

Preparation 29N-[3(1S,3S)-3-(2-aminoethyl)cyclopentyl](t-butoxy)carboxamide

[0452] 0.5 g (2.2 mmols) of a compound from preparation 14 was reducedwith 0.065 g of PtO₂ in EtOH (50 mL) at 60 psi of H₂ at 40° C. over 12h. The catalyst was removed by vacuum filtration, and the solvent wasremoved in vacuo to yield 0.421 g of the title compound. MS(ES+)mtz=229.

Preparation 30N-{(1S,3S)-3-[2-(Phenylcarbonylamino)ethyl]cyclopentyl}(t-butoxy)carboxamide

[0453] In a manner similar to the acylation of a compound frompreparation 24, 0.172 g (0.75 mmol) of a compound from preparation 29was acylated with benzoyl chloride and the residue formed waschromatographed on silica gel with hexane/ethyl acetate 2:1 to yield0.127 g of the title compound. MS(ES+)m/z=333.

Preparation 31N-{(1S,3S)-3-[2-(Phenylcarbonylamino)ethyl]cyclopentyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazo]4-yl]carboxamide

[0454] In a manner similar to preparation 17, 0.127 g (0.36 mmol) of acompound from preparation 30 was deprotected, followed by acylation with3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride in thesame manner as the preparation of a compound from preparation 12 toyield 0.15 g of the title compound. MS(ES+)m/z=470.

Preparation 32N-((1S,3S)-3-{2-[(3,4,5-Trimethoxyphenyl)carbonylamino]ethyl}cyclopentyl)(t-butoxy)carboxamide

[0455] In the same manner as preparation 30, 0.1 g (0.44 mmol) of acompound from preparation 29 was acylated with 3,4,5-trimethoxybenzoylchloride to yield 0.16 g of the title compound. MS(ES+)m/z=423.

Preparation 33N-{(1S,3S)-3-[2-((3,4,5-Trimethoxyphenyl)carbonylamino)ethyl]cyclopentyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

[0456] In a manner similar to preparation 31, 0.16 g (0.38 mmol) of acompound from preparation 32 yielded 0.174 g of the title compound.MS(ES+)m/z=560.

Preparation 34((3S,1R)-3-{[(t-Butoxy)carbonylamino]methyl}cyclopentyl)-N-(3,4,5-trimethoxyphenyl)carboxamide

[0457] In a manner similar to the preparation of a compound frompreparation 16, 0.224 g (0.92 mmols) of a compound from preparation 20was converted to 0.34 g of the title compound. MS(ES+)m/z=409.

Preparation 35[(3S,1R)-3-(aminomethyl)cyclopentyl]-N-(3,4,5-trimethoxyphenyl)carboxamide

[0458] In a manner similar to preparation 17, 0.049 g (0.12 mmol) of acompound from preparation 34 was deprotected with TFA to yield 0.013 gof the title compound. MS(ES+)m/z=308.

Preparation 36[(3S,1R)-3-({[3-2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}methyl)cyclopentyl)-N-(3,4,5-trimethoxyphenyl)carboxamide

[0459] In a manner similar to preparation 18, 0.013 g (0.042 mmol) of acompound from preparation 35 was converted to a residue which waschromatographed on silica gel with dichloromethane 100% todichloromethane/MeOH 2% to yield 0.018 g of the title compound.MS(ES+)m/z=545.8.

Preparation 37 Ethyl2-(3-{[4-(2-chloro-6-fluorophenyl)₂-methyl-3-furyl]carbonylamino}cyclohexyl)acetate

[0460] To a solution of 3-nitrophenylacetic acid, 1.0 g (5.5 mmol) in 90mL of ethanol was added 1.0 g of PtO₂ and 2 mL of 5N HCl. The mixturewas hydrogenated overnight at 60° C. and 60 psi, filtered through celiteand concentrated to dryness. To a solution of the residue in 15 mL ofdichloromethane was added 3.0 mL (21.6 mmol) of triethylamine and 2.0 g(7.2 mmol) of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonylchloride. The solution was stirred overnight at ambient temperature.Chloroform was added and the solution was washed with 0.5N HCl,saturated sodium bicarbonate, brine, dried over sodium sulfate, filteredand concentrated to dryness. The residue was chromatographed on silicagel using 5% acetone/dichloromethane as eluent to yield 2.0 g (66%) ofthe desired mixture of isomers as a white solid. ¹H-NMR is consistentwith structure. MS (ion spray) 423.2 (M+1).

Preparation 38 Ethyl2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]acetate

[0461] To a solution of a compound from preparation 37, 1.0 g (2.4 mmol)in 20 mL of N,N-dimethylformamide was added 0.35 g (3.1 mmol) ofpotassium t-butoxide. After 75 min, the mixture was poured into 1NHCl/ice and extracted with ethyl acetate. The combined organics werewashed with brine, dried over sodium sulfate, filtered and concentratedto dryness. The residue was chromatographed on silica gel using 5%acetone/dichloromethane as eluent to yield 0.65 g (67%) of the desiredmixture of isomers as a viscous yellow oil. ¹H-NMR is consistent withstructure. MS (ion spray) 403.3 (M+1).

Preparation 392-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]aceticacid

[0462] To a solution of a compound from preparation 38, 0.65 g (1.5mmol) in 10 mL of tetrahydrofuran and 10 mL of ethanol was added 3.0 mL(15.0 mmol) of 5N sodium hydroxide. After 40 min at ambient temperature,the reaction was concentrated to dryness. The residue was partitionedbetween ethyl acetate and water, was acidified to pH 3.0 with 1N HCl,and was extracted with ethyl acetate. The combined organics were washedwith brine, dried over sodium sulfate, filtered and concentrated todryness to yield 0.53 g (93%) of the desired mixture of isomers as awhite foam. ¹H-NMR is consistent with structure. MS (ion spray) 375.2(M+1).

Preparation 40 Methyl 2-(3-nitrocyclohexyl)acetate

[0463] To a solution of m-nitrophenylacetic acid, 14.2 g (78.0 mmol) in200 mL of methanol at 0° C. was added 20 mL of acetyl chloride dropwise.The reaction mixture was stirred overnight at ambient temperature andconcentrated to dryness. The residue was chromatographed on silica gelusing 50% ethyl acetate/hexanes as eluent to yield 14.7 g (97%) of thedesired mixture of isomers as a yellow oil. ¹H-NMR is consistent withstructure. MS (FD) 194.8 (M−1).

Preparation 41 Methyl2-(3-{[4(2-chloro-6-fluorophenyl)-2-methyl-3-furyl]carbonylamino}cyclohexyl)acetate

[0464] To a solution of methyl 2-(3-nitrocyclohexyl)acetate (13.8 g,71.0 mmol) in 200 mL of acetic acid was added 6.9 g of PtO₂. The mixturewas hydrogenated overnight at ambient temperature and 60 psi, then wasfiltered through celite and concentrated to dryness. To a solution ofthe residue, 8.8 g (38.0 mmol) in 200 mL of dichloromethane was added 27mL (190 mmol) of triethylamine and 10.4 g (38.0 mmol) of3-(2-chloro-6-fluorophenyl)-5-methylisoxazole carbonyl chloride. Themixture was stirred overnight at ambient temperature then chloroform wasadded. The organics were washed with 0.5N HCl, saturated sodiumbicarbonate, brine, dried over sodium sulfate, filtered and concentratedto dryness. The resulting residue was chromatographed on silica gelusing 5% acetone/dichloromethane to yield 4.43 g (29%) of the desiredmixture of isomers as a colorless, viscous oil. ¹H-NMR is consistentwith structure. MS (ion spray) 409.2 (M+1).

Preparation 422-(3-{[4-(2-Chloro-6-fluorophenyl)-2-methyl-3-furyl]carbonylamino}cyclohexyl)aceticacid

[0465] To a solution of a compound from preparation 41, 1.2 g (3.0 mmol)in 20 mL of absolute ethanol and 20 mL of tetrahydrofuran was added 6.0mL (30.0 mmol) of 5N sodium hydroxide. The mixture was stirred 4 h, thenthe organics were concentrated off. The remaining aqueous phase wasacidified to pH 3.0 with 1N HCl, then extracted with ethyl acetate. Thecombined organics were washed with brine, dried over sodium sulfate,filtered and concentrated to dryness. The residue was dissolved inchloroform and concentrated to dryness to yield 1.0 g (84%) of thedesired mixture of isomers as a white foam. ¹H-NMR is consistent withstructure. MS (ion spray) 393.2 (M−1).

Preparation 43[4-(2-Chloro-6-fluorophenyl)-2-methyl(3-furyl)]-N-{3-[2-(4-methylpiperidyl)-2-oxoethyl]cyclohexyl}carboxamide

[0466] To a solution of a compound from preparation 42, 1.0 g (2.6 mmol)in 10 mL of N,N-dimethylformamide was added 0.34 mL (2.9 mmol) of4-methylpiperidine, 0.43 g (3.1 mmol) of 1-hydroxy-7-azabenzotriazbleand 0.6 g (3.1 mmol) of1-(3-(dimethyl-amino)propyl)-3-ethylcarbodiimide. The mixture wasstirred overnight at ambient temperature and concentrated to dryness.The resulting residue was partitioned between ethyl acetate and waterand was extracted with ethyl acetate. The combined organics were washedwith brine, dried over sodium sulfate, filtered and concentrated todryness. The residue was chromatographed on silica gel using a gradientof 30% ethyl acetate/hexanes to 5% methanol/chloroform as eluent toyield 0.9 g (70%) of the desired mixture of isomers as a white foam.¹H-NMR is consistent with structure. MS (ion spray) 476.2 (M+1).

Preparation 445-[(3S,1R)-3-(Aminomethyl)cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0467] A solution of a compound from preparation 54 (enantiomer 2) (6.6g (14.8 mmol) in 230 mL of acetic acid saturated with hydrochloric acidwas stirred for 2 h at ambient temperature, then was concentrated todryness. The resulting residue was partitioned between 20%isopropanol/chloroform and saturated sodium bicarbonate and wasextracted with 20% isopropanol/chloroform. The combined organics werewashed with brine, dried over sodium sulfate, filtered and concentratedto dryness to yield 4.68 g (92%) of the desired product as a yellowsolid. ¹H-NMR is consistent with structure. MS (ion spray) 346.1 (M+1).

Preparation 45Phenylmethyl-2-{(3S,1R)-3-[(t-butoxy)carbonylamino]cyclohexyl}acetate

[0468] To a solution of phenylmethyl2-((3S,1R)-3-azidocyclohexyl)acetate, 5.0 g (18.3 mmol) in 350 mL ofethyl acetate under a nitrogen atmosphere was added 8.0 g (36.6 mmol) ofBOC-anhydride and 2.0 g of Lindlar's catalyst. The nitrogen was purgedwith hydrogen and the reaction mixture was stirred overnight under ahydrogen balloon, then concentrated to dryness. The resulting residuewas filtered through celite and chromatographed on silica gel usingethyl acetate/hexanes as eluent to yield 6.25 g (98%) of the desiredproduct as a clear oil which solidifies upon standing. ¹H-NMR isconsistent with structure. MS (ion spray) 347 (M+).

Preparation 46 Phenylmethyl2-((3S,1R)-3-{[4-(2-chloro-6-fluorophenyl)-2-methyl(3-furyl)lcarbonylamino}cyclohexyl)acetate

[0469] To a solution of a compound from preparation 45, 5.05 g (20.4mmol) in 80 mL of dichloromethane at 0° C. was added 3.7 mL (24.5 mmol)of triethylamine and 10 mg of 4-dimethylaminopyridine, followed by 6.15g (22.4 mmol) of 3-(2-chloro-6fluorophenyl)-5-methylisoxazole-4-carbonyl chloride. The reactionmixture was stirred overnight while warming to ambient temperature, andwas then washed with 0.1N hydrochloric acid, washed with brine, driedover sodium sulfate, filtered and concentrated to dryness. The residuewas chromatographed on silica gel using ethyl acetate/hexanes as eluent,concentrated to dryness, dissolved in chloroform and concentrated todryness to yield 5.74 g (58%) of the desired compound as a white solid.¹H-NMR is consistent with structure. MS (ion spray) 485.5 (M+1).

Preparation 472-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]aceticacid

[0470] To a solution of a compound from Example 491 (3.91 g, 8.4 mmol)in 70 mL of dioxane was added 70 mL (350 mmol) of 5N sodium hydroxide.The mixture was refluxed for 4 h and was cooled to ambient temperatureand acidified to pH 1 with 5N hydrochloric acid. The resulting mixturewas extracted with 20% isopropanol/chloroform. The combined organicswere washed with brine, dried over sodium sulfate, filtered andconcentrated to dryness. The residue was triturated in ether, filteredand dried under vacuum to yield 1.8 g (57%) of the desired product as atan solid. ¹H-NMR is consistent with structure. MS (ion spray) 374.8(M+).

Preparation 48cis-N-[3-Aminomethylcyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0471] A slurry of a compound from preparation 52, 1.2 g (2.7 mmol) in20 mL of acetic acid saturated with hydrochloric acid was stirred for 4h at ambient temperature, then concentrated to dryness. The residue wasdissolved in toluene and concentrated to dryness. The residue wasslurried in ether/hexanes, concentrated to dryness, and dried undervacuum to yield 750 mg (80%) of the title compound as a tan solid.¹H-NMR is consistent with structure. MS (ion spray) 346.2 (M+1).

Preparation 49 (t-Butoxy)N-[(3-nitrophenyl)methyl]carboxamide

[0472] To a suspension of 5.00 g (26.5 mmol) of 3-nitrobenzylaminehydrochloride in 100 mL CH₂Cl₂ at room temperature was added 5.79 g(26.5 mmol) of di-t-butyl dicarbonate. To this was added 8.13 mL (58.3mmol) of triethylamine, dropwise over 15 min. The reaction was stirredfor 3 h at room temperature, after which it was diluted with 300 mL ofethyl acetate. The resulting organic solution was washed three timeswith 1N HCl solution, dried over sodium sulfate and concentrated invacuo to give 6.2 g (93%) of a white solid, which was characterized asthe title compound. MS (F/A) m/z=253.

Preparation 50 (t-Butoxy)-N-[(3-aminocyclohexyl)methyl]carboxamide

[0473] To a solution containing 12.0 g (47.7 mmol) of a compound frompreparation 49 in 300 mL ethanol was added 6.0 g of rhodium on carbon.The reaction was subjected to hydrogenation (60 psi) at 60° C. for 18 h,after with the catalyst was removed by vacuum filtration and the solventremoved in vacuo, giving 9.5 g (87%) of a clear oil. This material wascharacterized as the title compound and used without furtherpurification.

Preparation 51 N-(3{[t-Butoxy)carbonylamino]methyl}cyclohexyl)[4-(2-chloro-6-fluorophenyl)-2-methyl(3-furyl)]carboxamide

[0474] To a solution of 9.5 g (41.6 mmol) of a compound from preparation50 in 200 mL of CH₂Cl₂ was added 11.4 g (41.6 mmol) of3-(2-chloro-6-fluorophenyl)-5-methyl-isoxazole-4-carbonyl chloride,followed by 11.6 mL (83.2 mmol) of triethylamine at room temperature.The reaction was stirred at room temperature for 15 h, and concentratedin vacuo. The crude solid was dissolved in 200 mL of ethyl acetate andthe organic solution was washed twice with 1N HCl solution, dried oversodium sulfate and concentrated in vacuo to give a yellow solid. Thismaterial was recrystallized from methanol to give 12.5 g (64%) of awhite crystalline solid, which was characterized as the title compound,as an inseparable mixture of cis and trans isomers. MS(FIA) m/z=466.2.

Preparation 52 and 53(t-Butoxy)-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}carboxamide

[0475] To a stirred solution of 7.00 g (15.0 mmol) of a compound frompreparation 51 in 200 mL of DMF at room temperature was added 30.0 mL(15 mmol) of a 0.5 M toluene solution of potassium bis(trimethylsilyl)amide over 10 min. The resulting dark red reaction was stirred anadditional 5 min at room temperature and added to 200 mL of 1N HCl. Thetwo phase solution was diluted with 400 mL of ethyl acetate and theorganic layer was separated. The organic solution was washed four timeswith brine, dried over sodium sulfate and concentrated in vacuo to givean orange solid. This material was recrystallized from toluene to give3.4 g of a light yellow solid, which was characterized as pure racemiccis material, 52: MS(FIA) m/z=446.1. Purification of the racemic transmaterial (53) was accomplished by concentrating the mother liquor andsubjecting this material to flash chromatography on silica gel, using50% hexane-ethyl acetate as the eluant. The major fractions werecombined to give a light yellow solid, which was characterized as pureracemic trans material: MS(FIA) m/z=446.1.

Preparation 54N-{3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-y))cyclohexyl]methyl}(t-butoxy)carboxamide

[0476] The racemic cis material from a compound from preparation 52 wasseparated into its enantiomers by chiral HPLC chromatography using aChiralpak AD column and 10% ethyl alcohol-heptane as the eluant at aflow of 1.0 mL/min.

[0477] Retention Time (Enantiomer 1)=10.501 min.

[0478] Retention Time (Enantiomer 2)=12.576 min.

Preparation 55 Methyl 3-[4-methoxyphenyl)methoxy]benzoate

[0479] To a solution containing 5.00 g (32.9 mmol) of methyl3-hydroxybenzoate in 100 mL of DMF was added 4.77 mL (32.9 mmol) ofp-methoxybenzyl chloride and 4.54 g (32.9 mmol) of anhydrous potassiumcarbonate. The reaction was stirred at room temperature for 16 h,followed by 1 h at 100° C. The solution was diluted with 200 mL of ethylacetate and 200 mL of 1N HCl. The organic phase was separated and washedfive times with brine, dried over sodium sulfate and concentrated invacuo to give 8.99 g of a white amorphous solid, which was characterizedas the title compound. This material was used without furtherpurification.

Preparation 56 3-[(4-Methoxyphenyl)methoxy]benzoic acid

[0480] To a solution containing 2.75 g (10.0 mmol) of a compound frompreparation 55 in 50 mL of MeOH was added 10 mL of 1N NaOH solution. Toaid solubility, 20 mL of THF was added and the reaction was heated atreflux for 3 h. The reaction was cooled to room temperature and dilutedwith 100 mL of ethyl acetate and 100 mL of 1N HCl solution. The organiclayer was separated, dried over sodium sulfate and concentrated in vacuoto give 2.45 g of a white amorphous solid, which was characterized asthe title compound. This material was used without further purification.

Preparation 57 (−)-(1R,cis)-Pinonic acid

[0481] A solution of 1S-(−)-pinene (11.95 mL, 75 mmol) in methanol (50mL) and chloroform (50 mL) at −78° C. was treated with ozone for 2 h viaa gas dispersion tube. After purging with nitrogen for 1 h, methylsulfide (16.5 mL, 225 mmol) was added, and the reaction was allowed towarm to room temperature overnight. The solvent was removed in vacuo andthe residue dissolved in diethyl ether, washed with water, saturatedaqueous brine solution, dried over magnesium sulfate and concentrated toapproximately 11 g of yellow liquid. The liquid was dissolved in ethylether and treated with oxygen for 2 h, followed by stirring under an O₂balloon overnight. The reaction was concentrated to give 12.42 g as aslightly yellow liquid, 90% yield. ¹H NMR: consistent with structure. MS(ion spray) 183 (M−1).

Preparation 58 (3-Acetylamino-2,2-dimethylcyclobutyl)acetic acid

[0482] To a solution of a compound from preparation 57 (12.37 g, 67.1mmol) in acetic acid (270 mL) was added hydroxylamine-O-sulfonic acid(11.74 g, 100.7 mmol), and the reaction was heated to reflux undernitrogen for 20 h. The reaction was concentrated and the residuedissolved in 2N HCl, followed by extraction with ethyl acetate (×4). Thecombined organics were washed with brine, dried over magnesium sulfate,and concentrated. The brown solution was treated with decolorizingcharcoal, filtered through celite, and concentrated to 5.85 g as a lightyellow oil, 44% yield. ¹H NMR: consistent with structure. MS (ion spray)200 (M⁺+1), 198 (M⁺−1).

Preparation 59 (3-Acetylamino-2,2-dimethylcyclobutyl)acetic acid methylester

[0483] To a 0° C. flask of methanol (150 mL) was added thionyl chloride(10.7 mL, 146.8 mmol) dropwise via an addition funnel. To this solutionwas added a compound from preparation 58 (5.85 g, 29.4 mmol) dropwise asa solution in methanol (100 mL). The cooling bath was removed and thereaction allowed to stir at room temperature for 2 h. The reaction wasconcentrated to a brown oil, dissolved in ethyl acetate, washed withsaturated aqueous sodium bicarbonate solution, brine, dried overmagnesium sulfate and concentrated to a 5.5 g of a brown oil.Purification by column chromatography on silica gel (eluting with50-100% ethyl acetate/hexane) gave 3.1 g as a brown oil, 50% yield. ¹HNMR: consistent with structure. MS (ion spray) 213 (M⁺).

Preparation 60 (3-Amino-2,2-dimethylcyclobutyl)acetic acid methyl ester

[0484] A compound from preparation 59 (3.09 g, 14.5 mmol) was dissolvedin 2N HCl (100 mL) and heated to reflux for 18 h, then concentrated. Toa 0° C. flask of methanol (100 mL) was added thionyl chloride (5.3 mL,72.4 mmol) dropwise via an addition funnel. To this solution was addedthe crude material dropwise as a solution in methanol (15 mL). The clearsolution was allowed to warm to room temperature overnight. The solutionwas concentrated, and purification by SCX column (eluting withtetrahydrofuran/water then ammonia/methanol) gave 2.52 g as a brownsolid, 100% yield. ¹H NMR: consistent with structure. MS (ion spray) 172(M⁺+1).

Preparation 61(3-{[3-(2-Chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl]amino}-2,2-dimethyl-cyclobutyl)aceticacid methyl ester

[0485] To a solution of a compound from preparation 60 (566 mg, 3.31mmol) in dichloromethane (20 mL) was added3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (1.09g, 3.97 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol), andtriethylamine (1.4 mL, 9.92 mmol) dropwise via syringe. The solution wasstirred under nitrogen at room temperature overnight. The solution waswashed with 1.0N HCl (×3), saturated aqueous sodium bicarbonatesolution, brine, dried over magnesium sulfate and concentrated.Purification by flash chromatography on silica gel (eluting with 2040%ethyl acetate/hexane) gave 1.28 g as a yellowish oil, 95% yield. ¹H NMR:consistent with structure. MS (ion spray) 409 (M+).

Preparation 62[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-2,2-dimethyl-cyclobutyl]-aceticacid methyl ester

[0486] To a 0° C. solution of a compound from preparation 61 (2.44 g,5.97 mmol) in dimethylformamide (100 mL) was added potassium t-butoxide(0.80 g, 7.16 mmol). After 15 min. the reaction was quenched with 1.0NHCl and extracted with 20% isopropanol/chloroform. The organic layer wasthen washed with 1.0N HCl (×2), saturated aqueous sodium bicarbonatesolution, brine, dried over magnesium sulfate and concentrated.Purification by flash chromatography on silica gel (eluting with 15-20%ethyl acetate/hexane) gave 739 mg (32% yield) as a white solid. ¹H NMR:consistent with structure. MS (ion spray) 389 (M+).

Preparation 63[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-2,2dimethyl-cyclobutyl]acetic acid

[0487] A solution of a compound from preparation 62 (737 mg, 1.89 mmol)in 5N NaOH (25 mL) was heated to reflux for 1 h. The solution wasconcentrated, dissolved in 20% isopropanol/chloroform, acidified to pH 2with 5N HCl, washed with 1.0N HCl (×2), dried over magnesium sulfate andconcentrated to give 519 mg as a light orange foam, 73% yield. ¹H NMR:consistent with structure.

Preparation 64[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c<quinolin-5-yl)-2,2-dimethyl-cyclobutylmethyl]carbamicacid 2-trimethylsilanylethyl ester

[0488] To a mixture of a compound from preparation 63 (318.7 mg, 0.85mmol) in toluene (15 mL) was added triethylamine (130 μL, 0.94 mmol),diphenylphosphorylazide (202 μL, 0.94 mmol), and the mixture heated toreflux for 3 h. To the reaction was added 2-(trimethylsilyl)-ethanol(183 μL, 1.28 mmol), and the mixture heated at reflux overnight. Thesolution was concentrated and dissolved in dichloromethane, washed with1.0N HCl, brine, dried over magnesium sulfate and concentrated.Purification by flash chromatography on silica gel (eluting with 0-30%ethyl acetate/hexane) gave 144 mg as a white foam, 35% yield. ¹H NM:consistent with structure. MS (ion spray) 490 (M⁺).

Preparation 65N-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylaminol}cyclohexyl)(t-butoxy)carboxamide

[0489] To a 0° C. solution of 1,3-diaminocyclohexane (50.56 g, 442.8mmol) in chloroform (850 mL) was added a solution ofdi-t-butyl-dicarbonate (20.3 mL, 88.6 mmol) in chloroform (250 mL)dropwise via an addition funnel over 25 minutes. The mixture was stirredunder nitrogen at room temperature overnight. The reaction was washedwith saturated aqueous sodium bicarbonate solution (3×), brine, driedover magnesium sulfate, and concentrated to give 17.58 g of a white oil.To a solution of the crude material (17.58 g, 82.0 mmol) indichloromethane (500 mL) was added3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (23.65g, 86.1 mmol), dimethylaminopyridine (1.00 g, 8.2 mmol), andtriethylamine (34.3 mL, 246.1 mmol) dropwise via syringe. The solutionwas stirred under nitrogen at room temperature overnight. The solutionwas washed with 0.1N HCl (2×), saturated aqueous sodium bicarbonatesolution (2×), brine, dried over magnesium sulfate and concentrated. Theorange solids were treated with ethyl ether, sonicated for 15 minutes,and filtered. The resulting white solids were crushed, treated withethyl ether, sonicated for 15 minutes, filtered out, and dried on avacuum overnight to give 16.20 g of the title racemic cis compound as awhite solid, 87% yield based on a 1:1 mixture of cis:trans. Thismaterial was then separated by chiral LC on a Chiralcel OD column toyield 9 g of isomer 1: (3S,1R) and 7 g of isomer 2: (1S,3R). ¹H NMR:consistent with structure. MS (ion spray) 352 (1-BOC+1).

Preparation 66N-(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl](t-butoxy)carboxamide

[0490] To a solution of a compound from preparation 65 (isomer 1) (500mg, 1.11 mmol) in dimethylformamide (20 mL) was added KHMDS (3.3 m]L,1.66 mmol, 0.5M in toluene) rapidly via syringe. After 15 minutes, ethylacetate (50 mL) was added to the reaction, and the solution added to aseparatory funnel containing water (50 mL) and brine (30 mL). The layerswere separated, and the aqueous layer was extracted with ethyl acetate(×2). The combined organics were washed with brine, dried over magnesiumsulfate, and concentrated to give 709 mg red solid. Purification usingflash chromatography on silica gel (eluting with 20-30% ethylacetate/hexane) gave 205 mg of the title compound as a yellow solid, 43%yield. ¹H NMR: consistent with structure. MS (ion spray) 332 (M⁺−BOC).

Preparation 67N-(3S,1R)-3-(9-chloro-3-methyl-4-oxo-H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl](t-butoxy)carboxamide

[0491] To a solution of a compound from preparation 65 (isomer 2) (500mg, 1.11 mmol) in dimethylformamide (20 mL) was added KHMDS (3.3 mL,1.66 mmol, 0.5M in toluene) rapidly via syringe. After 4 minutes, ethylacetate (50 mL) was added to the reaction, and the solution added to aseparatory funnel containing water (50 mL) and brine (30 mL). The layerswere separated, and the aqueous layer was extracted with ethyl acetate(2×). The combined organics were washed with brine, dried over magnesiumsulfate, and concentrated to give 700 mg red solid. Purification usingflash chromatography on silica gel (eluting with 0-0.5%methanol/chloroform) gave 372 mg of the title compound as a yellowsolid, 78% yield. ¹H NMR: consistent with structure. MS (ion spray) 332(M⁺−BOC).

Preparation 685-((3S,1R)-3-Aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydrochloride

[0492] To a compound from preparation 66 (200 mg, 0.46 mmol) was addedacetic acid saturated with HCl_((g)) (10 mL, ˜3N in HCl) and thesolution stirred vigorously at room temperature for 1 h. The reactionwas concentrated, followed by addition of acetonitrile and concentratedto assist in the removal of acetic acid. The resulting white solid wastreated with ethyl ether, sonicated, and filtered to yield 159 mg of thetitle compound as a white solid, 93% yield. ¹H NMR: consistent withstructure. MS (ion spray) 369 (M⁺).

Preparation 695-((1S,3R)-3-aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydrochloride

[0493] To a compound from preparation 67 (368 mg, 0.85 mmol) was addedacetic acid saturated with HCl_((g)) (15 mL, ˜3N in HCl) and thesolution stirred vigorously at room temperature for 1 h. The reactionwas concentrated, followed by addition of acetonitrile and concentratedto assist in the removal of acetic acid. The resulting white solid wastreated with ethyl ether, sonicated, and filtered to yield 249 mg of thetitle compound as a white solid, 79% yield. ¹H NMR: consistent withstructure. MS (ion spray) 369 (M⁺).

Preparation 70 Ethyl 4-aminohexanecarboxylate

[0494] Thionyl chloride (3.0 mL, 0.041 mol) was added dropwise toethanol (125 mL) at room temperature and the mixture stirred for anadditional 10 min. Then, 4-amino-1-cyclohexane-carboxylic acid (5.0 g,0.035 mol) was added and the mixture stirred overnight at ambienttemperature. The mixture was then concentrated in vacuo and theresulting solid dried overnight in vacuo which resulted in the isolationof 6.84 g (94%) of the desired ester hydrochloride. MS(ES): (M+1)+172.2m/z.

Preparation 71 Ethyl4-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexanecarboxylate

[0495] A compound from preparation 70 (0.414 g, 0.002 mol) was combinedwith 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride(0.548 g, 0.002 mol) and triethylamine (0.70 mL, 0.005 mol) in CH₂Cl₂(6.0 mL) and the mixture stirred for 5 h at ambient temperature. Themixture was diluted with CH₂Cl₂, washed with 2× water, and dried oversodium sulfate. The mixture was concentrated in vacuo. The resultingresidue chromatographed over silica gel using CH₂Cl₂/MeOH as eluantwhich allowed for isolation of 0.790 g (97%) of the desired amide.MS(ES): (M+1)⁺ 409.3, 410.3, 411.2

Preparation 72 Ethyl4-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylate

[0496] A compound from preparation 71 (0.70 g, 0.0017 mol) was dissolvedin DMF (10 mL) and potassium-t-butoxide (0.230 g, 0.0020 mol) was addedand the mixture stirred for 2 h at ambient temperature. Water (100 mL)and aq 1N HCl (5 mL) was added and the aqueous mixture extracted withethyl acetate. The combined extracts were dried over sodium sulfate andthen concentrated in vacuo. The resulting residue was chromatographedover silica gel using CH₂Cl₂/MeOH as eluant which allowed for isolationof 0.540 g (81%) of product as a light yellow solid. MS(FS): (M+1)⁺389.2, 391.2 m/z.

Preparation 73 3-[(t-Butoxy)carbonylamino)cyclohexanecarboxylic acid

[0497] To 3-aminocyclohexane carboxylic acid (3.00 g, 0.021 mol) in aTHF/H₂O mixture (50 mL/50 mL) was added potassium carbonate (2.90 g,0.021 mol) and di-t-butyl dicarbonate (4.58 g, 0.021 mol) and theresultant mixture stirred overnight at ambient temperature. Then aqueous5N HCl (10 mL) was added and the mixture extracted with ethyl acetate.The combined extracts were dried over sodium sulfate and concentrated invacuo which allowed for isolation of 4.92 g (96%) of desired product asa white solid. MS(ES): (M+1)⁺ 244.5 m/z.

Preparation 74 (t-Butoxy)-N-[3-(hydroxymethyl)cyclohexyl]carboxamide

[0498] A compound from preparation 73 (4.00 g, 0.0165 mol) was dissolvedin dry THF (50 mL) and the mixture cooled in an ice bath under anitrogen atmosphere. Then borane-tetrahydrofuran (1.0 M, 20 mL, 0.02mol) was added via syringe and the mixture stirred overnight whilewarning to room temperature. The reaction mixture was quenched into icewater and solid NaCl was added. This mixture was extracted with ethylacetate and the combined extracts were dried over sodium sulfate andconcentrated in vacuo. The resulting residue was chromatographed oversilica gel using a CH₂Cl₂/THF mixture as eluant which allowed forisolation of 2.40 g (63%) of the desired alcohol as a viscous oil.MS(ES): (M+1)⁺ 230.2 m/z.

Preparation 75(t-Butoxy)-N-[3-(p-toluenesulfonyloxymethyl)cyclobexyl]carboxamide

[0499] A compound from preparation 74 (0.15 g, 0.00066 mol) was combinedwith p-toluenesulfonyl chloride (0.125 g, 0.00066 mol), triethylamine(0.18 mL, 0.0013 mol), and DMAP (0.005 g, cat.) in dichloromethane (5.0mL) and the resultant mixture stirred overnight at room temperature. Themixture was then concentrated in vacuo and the residue chromatographedover silica gel using a mixture of CH₂Cl₂/THF as eluant which allowedfor the isolation of the desired product (0.195 g, 77%) as a thick oilthat solidified upon standing. MS(ES): (M+1)⁺ 384.2 m/z.

Preparation 76 (t-ButoxyN-[3-(phenylthiomethyl)cyclohexyl]carboxamide

[0500] Thiophenol (0.27 mL, 0.0026 mol) was dissolved in DMF (10 mL) atambient temperature under a nitrogen atmosphere and sodium hydride (60%,0.115 g, 0.0029 mol) was added. After stirring for 15 min., a compoundfrom preparation 75 was added and the mixture stirred overnight atambient temperature. The mixture was concentrated in vacuo and theresidue chromatographed over silica gel with CH₂Cl₂/THF as eluant whichallowed for isolation of 0.74 g (88%) of desired product as a whitesolid MS(ES): (M+1)⁺ 322.2 m/z.

Preparation 77 3-Phenylthiomethyl)cyclohexylamine

[0501] A compound from preparation 76 (0.50 g, 0.0016 mol) was dissolvedin CH₂Cl₂ (10 mL) and TFA (1.0 mL) was added After 1.5 h, deprotectionwas incomplete and additional TFA (1.0 mL) was added and the mixturestirred at ambient temperature for an additional 4 h. The mixture wasconcentrated in vacuo and the residue treated with aqueous NaHCO₃ andextracted with CH₂Cl₂. The combined extracts were concentrated in vacuoand the residue eluted over a short plug of silica gel (CH₂Cl₂/MeOH)which allowed for isolation of the desired amine (0.265 g, 77%). MS(ES):(M+1)+222.2 m/z.

Preparation 78[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-[3-(phenylthiomethyl)cyclohexyl]carboxamide

[0502] A compound from preparation 77 (0.26 g, 0.0012 mol) was combinedwith 3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride(0.322 g, 0.0012 mol) and triethylamine (0.33 mL, 0.0024 mol) in CH₂Cl₂(10 mL) and the mixture stirred overnight at ambient temperature. Thereaction mixture was chromatographed over silica gel using CH₂Cl₂/THF aseluant which allowed for isolation of 0.495 g (91%) of the desired amideas a white solid. MS(ES): (M+1)+459.4 m/z.

Preparation 79(t-Butoxy)N-[3-(phenylmethylthiomethyl)cyclohexyl]carboxamide

[0503] Benzyl mercaptan (0.31 mL, 0.0026 mol) was dissolved in DMF (10mL) at ambient temperature under a nitrogen atmosphere and sodiumhydride (60%, 0.115 g, 0.0029 mol) was added. After stirring for 15min., the compound from preparation 75 (1.00 g, 0.0026 mol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated in vacuo and the residue chromatographed over silicagel with CH₂Cl₂/THF as eluant which allowed for isolation of 0.80 g(92%) of desired product as a thick oil which solidified upon standing.MS(ES): (M+1)⁺ 336.2 m/z.

Preparation 80[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-[3-(phenylmethylthiomethyl)cyclohexyl]carboxamide

[0504] The compound from preparation 73 (0.40 g, 0.0012 mol) wasdissolved in CH₂Cl₂ (8.0 mL) and TFA (2.0 mL) and the mixture stirred atambient temperature for 3 h. The mixture was concentrated in vacuo andthe residue treated with aqueous NaHCO₃ and extracted with CH₂Cl₂. Thecombined extracts were dried over sodium sulfate and concentrated invacuo which allowed for the recovery of 0.19 g (68%) of crude amine.This amine (0.19 g, 0.0008 mol) was combined with3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride(0.22 g, 0.0008 mol) and triethylamine (0.23 mL, 0.0016 mol) in CH₂Cl₂(10 mL) and the mixture stirred overnight at ambient temperature. Water(−30 mL) was added and the mixture extracted with CH₂Cl₂. The combinedextracts were dried over sodium sulfate and then concentrated in vacuo.The resulting residue was chromatographed over silica gel usingCH₂Cl₂/THF as eluant which allowed for isolation of 0.29 g (77%) of thedesired amide as a white solid. MS(ES): (M+1)⁺ 473.1, 475.1 m/z.

Preparation 81 (t-Butoxy)-N-[3-{(benzylsulfonyl)methyl}cyclohexyl)carboxamide

[0505] A compound from preparation 79 (0.467 g, 0.0014 mol) wasdissolved in a methanol/acetone (10 mL)/(10 mL) mixture and NaHCO₃(0.467 g, 0.0056 mol) and water (10 mL) were added. Oxone® (1.71 g,0.0028 mol) was then added and the mixture stirred at ambienttemperature for 2.5 h. The mixture was concentrated in vacuo and theresidue taken up in water and extracted with CH₂Cl₂. The combinedextracts were dried over sodium sulfate and concentrated in vacuo. Theresulting residue was chromatographed over silica gel using CH₂Cl₂/THFas eluant which allowed for isolation of 0.420 g (82%) of the desiredsulfone as a white solid. MS(FD): M+367.2 m/z.

Preparation 82[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-(3-{benzylsulfonyl]methyl}cyclohexyl)carboxamide

[0506] The compound from preparation 81 (0.40 g, 0.0011 mol) and TFA(2.0 mL) were dissolved in CH₂Cl₂ (10.0 mL) and the mixture stirred atambient temperature for 2 h. t The mixture was concentrated in vacuo andthe residue treated with aqueous NaHCO₃ and extracted with CH₂Cl₂. Thecombined extracts were dried over sodium sulfate and concentrated invacuo which allowed for recovery of 0.21 g (71%) of crude amine. Thisamine (0.21 g, 0.0008 mol) was combined with3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride(0.22 g, 0.0008 mol), triethylamine (0.22 mL, 0.0016 mol) and DMAP(0.005 g, cat.) in CH₂Cl₂ (10 mL) and the mixture stirred overnight atambient temperature. The mixture was concentrated in vacuo and theresulting residue chromatographed over silica gel using CH₂Cl₂/THF aseluant which allowed for isolation of 0.35 g (89%) of the desired amide.MS(ES): (M+1)⁺ 505.1 m/z.

Preparation 83 {3-[(t-Butoxy)carbonylamino]cyclohexyl}methyl benzoate

[0507] The compound from preparation 74 (1.00 g, 0.0044 mol) wascombined with benzoyl chloride (0.56 mL, 0.0048 mol), triethylamine(1.70 mL, 0.012 mol), and DMAP (0.020 g, cat.) in CH₂Cl₂ (10 mL) and themixture stirred overnight at ambient temperature. The reaction mixturewas concentrated in vacuo and the residue chromatographed over silicagel using CH₂Cl₂/THF as eluant which allowed for isolation of 1.05 g(72%) of the desired ester as an oil. MS(ES): (M+1)+334.1 m/z.

Preparation 84(3-{[3-(2-Chloro-6-fluorophenyl)₅-methylisoxazol-4-yl]carbonylamino}cyclohexyl)methylbenzoate

[0508] The compound from preparation 83 (1.00 g, 0.003 mol) and TFA (2.0mL) were dissolved in CH₂Cl₂ (10 mL) and the mixture treated in a mannersimilar to preparation 82, which allowed for isolation of 0.69 g (98%)of crude amine. This amine (0.69 g, 0.0029 mol) was combined with3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (0.81g, 0.0029 mol) and triethylamine (0.82 mL, 0.0059 mol) in CH₂Cl₂ (10 mL)and again treated in a manner similar to preparation 81. Purificationresulted in the recovery of 1.30 g (95%) of desired amide as a whitefoam. MS(ES): (M+1)⁺ 471.1 m/z.

Preparation 859-Chloro-5-[3-(hydroxymethyl)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0509] The compound from Example 489 (0.33 g, 0.00073 mol) was added toaqueous sodium hydroxide (1N, 1.0 mL), ethanol (2.0 mL) and THF (2.0 mL)and the mixture stirred at ambient temperature for 3 h. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with 2× sat'd aq NaHCO₃ and dried over sodiumsulfate. Concentration in vacuo netted 0.225 g (88%) of desired alcoholas a tan foam. MS(ES): 347.2, 349.3 m/z.

Preparation 86 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic acid

[0510] A compound from preparation 45 (1.0 g; 2.77 mmol) was dissolvedin tetrahydrofuran (4 mL) and ethanol (4 mL) under a dry nitrogenatmosphere at room temperature. This cloudy white solution became clearand colorless after mixing with 2N NaOH(aq) (15 mL; 19.4 mmol; 11.1equiv) for 2 h. After rotary evaporation to dryness, the white solid wasdissolved in water (20 mL) and the resulting solution extracted withdiethyl ether (twice). Acidification of the aqueous layer to pH 2 with1N HCl(aq) produced a white solid that was extracted into ethyl acetate(thrice). The ethyl acetate was washed with saturated NaCl(aq), driedwith Na₂SO₄(s), and concentrated to dryness by rotary evaporation. Theresulting white solid (700 mg; 98% yield) was used in subsequentreactions without further purification. MS(ES) calc'd: [M+Na]⁺=280.2m/z, [M−H]⁻=256.2 m/z. Found: 280.1 m/z; 256.2 m/z.

Preparation 872-{3-[(t-Butoxy)carbonylamino)cyclohexyl}-N-ethoxy-N-methyl acetamide

[0511] A compound from preparation 86 (690 mg; 2.68 mmol) was dissolvedin anhydrous dichloromethane (10 mL) under a dry nitrogen atmosphere atroom temperature. Addition of 1,1′-carbonyldiimidazole (535 mg; 3.22mmol; 1.2 equiv) to the clear, colorless starting material solutionimmediately generated a gas. After stirring the resulting solution for30 min, triethyl amine (746 μL; 5.36 mmol; 2 equiv) andN,O-dimethylhydroxylamine hydrochloride (570 mg; 5.90 mmol; 2.2. equiv)were added and the solution stirred for 15 h. Water was added to thesolution and then the solution was extracted with dichloromethane(thrice). The organic layer was washed with saturated NaCl_((aq)), driedwith Na₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The resulting oil (850 mg) was purified by radialchromatography on a 4 mm thick silica gel rotor with a 5%tetrahydrofuran dichloromethane (v/v) mobile phase. A clear, colorlessoil (650 mg; 80%) was obtained. MS(ES) calc'd: [M+Na]⁺=323.2 m/z. Found:323.2 m/z.

Preparation 88(t-Butoxy)N-[3-(2-oxo-3-phenylpropyl)cyclohexyl]carboxamide

[0512] A compound from preparation 87 (4.11 g; 13.7 mmol) was dissolvedin anhydrous tetrahydrofran (100 mL) under a dry nitrogen atmosphere.The clear, colorless solution became clear and brown upon addition of0.5 M benzylmagnesium chloride in tetrahydrofran (15 mL; 30.1 mmol; 2.2equiv). The reaction was quenched with water (100 mL) after 0.5 h andthe product was extracted from the quenched solution with ethyl acetate.The organic layer was washed with saturated NaCl_((aq)) (once), driedwith Na₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The resulting oil was purified by silica gel chromatographyon a 6×15 cm column with a 2% acetonitrile/dichloromethane (v/v) mobilephase. A white solid (3.17 g; 70%) was obtained after concentration ofappropriate fractions. TOF-MS(ES) calc'd: [M+Na]⁺=354.2045 m/z. Found:354.2037 m/z.

Preparation 89[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-[3-(2-oxo-3-phenylpropyl)cyclohexyl]carboxamide

[0513] A compound from preparation 88 (3.0 g; 9.05 mmol) was dissolvedin excess, neat acetic acid saturated with HCl(G) (20 mL). After 30 minof stirring at room temperature, in air, the solution was concentratedto dryness by rotary evaporation. Acetic acid was removed from theresultant solid by consecutive dissolution in, and drying from,acetonitrile (thrice) and then diethyl ether (once). The resulting whitepowder was dissolved in anhydrous dichloromethane (400 mL) under anitrogen atmosphere. First was added3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (2.74g; 9.99 mmol; 1.1 equiv), and then 4-N,N-dimethylaminopyridine (114 mg;0.93 mmol; 0.1 equiv) and finally triethylamine (5 mL; 36.3 mmol; 4equiv). The reaction solution was stirred 17 h and then quenched withsaturated NaHCO_(3(aq)). The organic layer was washed with saturatedNaHCO_(3(aq)) (twice), saturated NaCl_((aq)) (once), dried withNa₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The resulting oil was dissolved in dichloromethane andpurified by column chromatography on a 6×15 cm silica gel bed indichloromethane. Dichloromethane (1 L) was followed by a 2%tetrahydrofuran/dichloromethane (v/v) mobile phase. A white solid (3.93g; 95%) was obtained. TOF-MS(ES) calc'd: [M+H]⁺=469.1694 m/z. Found:469.1692 m/z.

Preparation 90 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic acid

[0514] A compound from preparation 87 (845 mg; 2.81 mmol) was dissolvedin anhydrous tetrahydrofuran (30 mL) under a dry nitrogen atmosphere. A1 M solution of DIBAL-H in toluene (6.2 mL; 6.18 mmol; 2.2 equiv) wasadded dropwise to the −78° C. starting material solution over 5 min.After an additional 15 min of stirring, water quenched the cold reactionsolution. Extraction with ethyl acetate produced an emulsion that wasdestroyed by concentration of the solution to near dryness. Theresulting material was dissolved in water/diethyl ether and extractedwith diethyl ether without further complication. The organic layer waswashed with saturated NaCl(aq) (once), dried with Na₂SO_(4(s)),filtered, and concentrated to dryness by rotary evaporation. The productwas purified by radial chromatography on a 4 mm thick silica gel rotorwith 300 mL of 1% tetrahydrofuran/dichloromethane (v/v) mobile phasefollowed by 300 mL of 10% tetrahydrofuran/dichloromethane (v/v) mobilephase. A white solid (535 mg; 79%) was obtained after concentration ofthe desired fractions. MS(ES) calc'd: [M+H]⁺=264.1 m/z, [M-Boc+H]⁺=142.1m/z. Found: 264.1 m/z; 142.1 m/z.

Preparation 91N-{(1S,3S3-[2-(Phenylamino)ethyl]cyclohexyl}(t-butoxy)carboxamide

[0515] A nitrogen sparged round bottom flask was charged with denaturedethanol (5 mL), Ti(i-PrO)₄ (337 μL; 1.14 mmol; 2.2 equiv), and aniline(95 μL; 1.04 mmol; 2 equiv). A compound from preparation 90 (125 mg;0.518 mmol; 1 equiv) was then added to the clear, colorless reactionsolution. The reaction solution became cloudy and then progressed toclear and light yellow over 3.3 h. NaBH₄ (30 mg; 0.793 mmol; 1.5 equiv)was then added and allowed to react overnight at room temperature. Theclear, colorless reaction solution was quenched with 2 M NH_(3(aq)) (20mL). After a failed attempt at Celite® filtration, the product andCelite® mixture were suspended in water and extracted with CHCl₃(thrice). This organic layer was washed with saturated NaCl(aq) (once),dried with Na₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The aqueous layer was decanted from the Celite® and theCelite® was suspended in 2 M NH_(3(aq)) (120 mL). This suspension wasextracted with CHCl₃ (trice) and the organic layer was treated similarlyto the first organic layer. The combined extracts were purified byradial chromatography on a 2 mm thick silica gel rotor. The firstchromatography with a 2% tetrahydrofuran/dichloromethane (v/v) mobilephase did not completely purify the product and was followed by a secondand third radial chromatography with a 1%tetrahydrofuran/dichloromethane (v/v) mobile phase. A white solid (55mg; 33%) was obtained after concentration of the desired fractions.MS(ES) calc'd: [M+H]⁺=319.2 m/z; [M+C₂H₃O₂]⁻=317.2 m/z. Found: 319.2m/z; 377.2 m/z.

Preparation 92N-{(1S,3S)-3-[2-(Phenylamino)ethyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

[0516] A compound from preparation 91 (53 mg; 0.166 mmol) was dissolvedin excess, neat acetic acid saturated with HCl_((g)) (2 mL). After 30min of stirring at room temperature, in air, the solution wasconcentrated to dryness by rotary evaporation. Acetic acid was removedfrom the resultant solid by consecutive dissolution in, and drying from,acetonitrile (thrice) and then diethyl ether (twice). The resultingwhite powder was dissolved in anhydrous dichloromethane (8 mL) under anitrogen atmosphere. First was added3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (50.2mg; 0.183 mmol; 1.1 equiv), and then 4-N,N-dimethylaminopyridine (2 mg;0.017 mmol; 0.1 equiv) and finally triethylamine. (94 μL; 0.667 mmol; 4equiv). The reaction solution was stirred overnight, then quenched withsaturated NaHCO_(3(aq)), then extracted with dichloromethane (twice).The organic layer was washed with saturated NaCl_((aq)) (once), driedwith Na₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The resulting product was dissolved in dichloromethane andpurified by radial chromatography on a 2 mm thick silica gel rotor. Adichloromethane mobile phase was followed by a 5%tetrahydrofuran/dichloromethane (v/v) mobile phase. An off-white solid(66 mg; 87%) was obtained. TOF-MS(ES) calc'd: [M+H]⁺=456.1854 m/z.Found: 456.1850 m/z.

Preparation 93 Methyl2-(3-{[4(2-chloro-6-fluorophenyl)-2-methyl-3-furyl]carbonylamino}cyclohexyl)-acetate

[0517] Part a: To a solution containing 15.0 g (83 mmol) ofm-nitrophenylacetic acid in 200 mL ethanol was added 7.5 g 5% rhodium oncarbon. The reaction was subjected to hydrogenation (60 psi) at 60° C.for 10 hours, after which the catalyst was removed by vacuum filtrationand the solvent removed in vacuo, yielding 3.5 g (27%) of an oil. Thismaterial was used without further purification.

[0518] Part b: 1 mL acetyl chloride was added to 30 mL methanol. To thissolution was added 3.5 g (22.3 mmol) of a compound from part a and thereaction was stirred for 1 hour. Solvents were removed in vacuo,yielding 3.24 g (70%) of an oil. This material was used without furtherpurification.

[0519] Part c: To a solution of 1.05 g (5.06 mmol) of a compound frompart b in 10 mL of methylene chloride was added 1.53 g (5.57 mmol) of3-(2-chloro-6-fluoro-phenyl)-5methylisoxazole-4-carbonyl chloride,followed by 2.11 mL (15.2 mmol) of triethylamine at room temperature.The reaction was stirred overnight, then concentrated in vacuo. Thecrude solid was dissolved in 150 mL ethyl acetate, washed 3× with 1NHCl, 3× with NaHCO₃, 3× with brine, dried over sodium sulfate andconcentrated in vacuo yielding 1.8 g (87%) of a white solid. Thismaterial was an inseparable mixture of cis and trans isomers. MS(FIA)m/z=409.3

[0520] Part d: To a solution of 1.78 g (4.35 mmol) of a compound frompart c in 10 mL of DMF at room temperature was added 5 mL of 2N NaOH inMeOH. The reaction was stirred for 1 hour and 0.537 g (4.78 mmol) ofpotassium t-butoxide was added. The resulting dark red reaction wasstirred for 6 hours. The reaction was then added to 50 mL of 1N HCl anddiluted with 150 mL of ethyl acetate. The organic layer was separatedand washed 3× with brine, dried over sodium sulfate and concentrated invacuo. This crude material was purified by flash chromatography, elutingwith 5% MeOH/CH₂Cl₂. The major fractions were combined and concentratedin vacuo to give 1.15 g (71%) of a clear oil, which was characterized asthe title compound. MS(FIA) m/z=375.2

Preparation 942-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]aceticacid

[0521] To a solution of 1.78 g (4.35 mmol) of a product of preparation93, in 10 mL of DMF at room temperature was added 5 mL of 2N NaOH inMeOH. The reaction was stirred for 1 h and 0.537 g (4.78 mmol) ofpotassium t-butoxide was added. The resulting dark red reaction wasstirred for 6 h. The reaction was then added to 50 mL of 1N HCl anddiluted with 150 mL of ethyl acetate. The organic layer was separatedand washed 3× with brine, dried over sodium sulfate and concentrated invacuo. This crude material was purified by flash chromatography, elutingwith 5% MeOH/CH₂Cl₂. The major fractions were combined and concentratedin vacuo to give 1.15 g (71%) of a clear oil, which was characterized asthe title compound. MS(FIA) m/z=375.2.

Preparation 952-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]acetylchloride

[0522] To an ice bath cooled solution containing 0.75 g (2.0 mmol) acompound from preparation 94 in 10 mL methylene chloride and catalyticDMF (3 drops) was added 0.262 mL (3.0 mmol) of oxalyl chloride in oneportion. The ice bath was removed and the reaction stirred for 3 h. Thesolvents were removed in vacuo and the resulting oil azeotroped withtoluene. This material was characterized as the title compound and usedwithout further purification.

Preparation 96 Methyl 3-(azidomethyl)benzoate

[0523] To a solution of methyl 3-(bromomethyl)benzoate in DMF (55 ml)under N₂ was added sodium azide (10.39 g, 160 mmol) and stirred for 3 h.The solution was diluted with EtOAc, washed (water twice, then brine),dried (MgSO₄), filtered, and concentrated to give the title compound.This material was used without further purification. MS (EI+)(m/z)=101.1 [M⁺+1]

Preparation 97 Methyl 3-{[(t-butoxy)carbonylaminomethyl}benzoate

[0524] A mixture of a compound from preparation 95 (8.75 g, 45.8 mmol),(BOC)₂O (11.98 g, 55 mmol), 10% Pd/C catalyst (4.76 g), and EtOAc (175mL) was stirred under an atmosphere of hydrogen gas (balloon) for 18 h,filtered through celite, and concentrated. Column chromatography (silicagel, hexanes/EtOAc gradient) gave the title compound (5.8 g, 48%). MassSpectrum (ES+) (m/z) 166.0 [M−BOC].

Preparation 98 Methyl 3-{[(t-butoxy)carbonylamino]methyl}cyclohexanecarboxylate

[0525] A mixture of a compound from preparation 97 (5.57 g, 20 mmol), 5%Rh/C (2.78 g), and MeOH (140 mL) was shaken in a PARR apparatus at 60psi and 60° C. for 18 h, filtered through celite, and concentrated.Column chromatography (silica gel, hexanes/EtOAc gradient) gave thetitle compound (3.5 g, 62%). Mass Spectrum (ES+) (m/z) 166.0 [M−BOC].

Preparation 99 Methyl3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-5-yl]carbonylamino}cyclohexanecarboxylate

[0526] To a solution of a compound from preparation 98 (0.5 g, 1.845mmol) in dichloromethane (10 mL) was added TFA (7 mL) and stirred for 45min. The solution was concentrated using benzene to azeotrope. Theresidue was dissolved in dichloromethane (20 mL) and Et₃N (0.77 mL, 5.54mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonylchloride (0.56 g, 2.03 mmol) were added under N₂. The solution wasstirred overnight. The reaction was diluted with EtOAc, washed (0.1NHCl, H₂O, and brine), dried (MgSO₄), filtered, and concentrated. Columnchromatography (silica gel, hexanes/EtOAc gradient) gave the titlecompound (0.52 g, 69%). Mass Spectrum (FIA) (m/z) 409.3 [M+1].

Preparation 100 Methyl3(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylate

[0527] A compound from preparation 99 (0.445 g, 1.09 mmol) and t-BuOK(0.135 g, 1.2 mmol), in DMF (15 mL) were allowed to react for 15 minunder N₂. Ice water was added and extracted twice with EtOAc. Thecombined EtOAc layers were washed, dried, filtered, and concentrated.Column chromatography (silica gel, hexanes/EtOAc gradient) gave thetitle compound (0.329 g, 78%). Mass Spectrum (FIA) (m/z) 389.2 [M+1].

Preparation 101 Methyl3(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylate

[0528] A compound from preparation 100 (5.17 g, 12.7 mmol) and t-BuOK(1.56 g, 13.97 mmol), in DMF (130 mL) were allowed to react for 20 minunder N₂. Ice water was added and extracted twice with EtOAc. Thecombined EtOAc layers were washed, dried, filtered, and concentrated.Column chromatography (silica gel, acetone/dichloromethane gradient)gave cis (0.28 g, 7%), trans (1.08 g, 25%), and unseparated titlecompound (2.91 g, 68%).

[0529] Mass Spectrum (FIA) (m/z) 389.2 [M+1].

[0530] Mass Spectrum MM) (m/z) 389.2 [M+1].

Preparation 1023-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylate racemic

[0531] A cis compound from preparation 101 (1.08 g, 2.78 mmol), 1N NaOH(7 mL, 6.94 mmol), MeOH (20 mL), and THF (20 mL) were allowed to reactfor 5 h at 50° C. The reaction was cooled to room temperature, dilutedwith water, and acidified (conc. HCl) to less than pH 3. The mixture wasextracted with EtOAc (2×) and the combined extracts were washed, dried,filtered, and concentrated to give the title compound (1.03 g, 98%).Mass Spectrum (ES+) (m/z) 375.1 [M+1].

Preparation 103 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic acid

[0532] To a solution of a compound from preparation 45 (5.0 g, 14.4mmol), dioxane (96 ml), and 1.0 N NaOH (28.8 ml, 28.8 mmol) was heatedat 50° C. for 3 h. The reaction was cooled to room temperature, dilutedwith H₂O, and extracted with Et₂O. The aqueous layer was acidified(conc. HCl) to less than pH 3, and extracted with EtOAc (2×). Thecombined extracts were washed (brine), dried (MgSO₄), filtered, andconcentrated to give the title compound.

Preparation 104N-((1S,3R)-3-{[(Phenylmethoxy)carbonylamino]methyl}cyclohexyl)(t-butoxy)carboxamide

[0533] To a solution of a compound from preparation 103 (3.43 g, 13.35mmol), Et₃N (3.75 mL, 26.96 mmol) in toluene (86 mL) under N₂ was addedDPPA (5.8 mL, 26.96 mmol) and benzyl alcohol (4.28 mL, 41.38 mmol). Thesolution was heated to reflux overnight. The reaction was cooled to roomtemperature, diluted with EtOAc, washed (1.0N NaOH then brine), dried(MgSO₄), filtered, and concentrated. Column chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (3.05 g, 63%). MassSpectrum (ES+) (m/z) 263.1 [M−BOC].

Preparation 105N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}(t-butoxy)carboxamide

[0534] A mixture of a compound from preparation 104 (0.25 g, 0.69 mmol),benzoic anhydride (0.187 g, 0.828 mmol), 10% Pd/C catalyst (0.1 g), andEtOAc (10 mL) was stirred under an atmosphere of hydrogen gas (balloon)for 17 h. Added more benzoic anhydride (0.187 g, 0.828 mmol), and DMAP(0.025 g, 0.23 mmol), stirred for 2.5 h, filtered through celite, andconcentrated. Column chromatography (silica gel, hexanes/EtOAc gradient)gave the title compound (0.208 g, 91%). Mass Spectrum (FIA) (m/z) 333.2[M+1].

Preparation 106N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

[0535] In a fashion similar to that described for preparation 46, acompound from preparation 105 (0.1 g, 0.3 mmol), TFA (2.5 mL),dichloromethane (4 mL),3-(2,6-difluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (0.13 g,0.5 mmol), and Et₃N (0.125 mL, 0.9 mmol) gave the title compound (0.109g, 80%) after column chromatography (silica gel, hexanes/EtOAcgradient). Mass Spectrum (ES+) (m/z) 454.2 [M+1].

Preparation 107N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-phenylisoxazol-4-yl]carboxamide

[0536] In a fashion similar to that described for preparation 46, acompound from preparation 103 (0.1 g, 0.3 mmol), TFA (2.5 mL),dichloromethane (4 mL),3-(2-chloro-6-fluoro-phenyl)-5-phenyl-isoxazole-4-carbonyl chloride(0.15 g, 0.45 mmol), and Et₃N (0.125 mL, 0.9 mmol) gave the titlecompound (0.14 g, 88%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 532.1[M+1].

Preparation 108N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[5-2-fluorophenyl)(1,3-oxazol-4-yl)]carboxamide

[0537] A solution of a compound from preparation 105 (0.1 g, 0.3 mmol)in TFA (2 mL) was stirred for 1.5 h. The solution was concentrated usingbenzene to azeotrope, diluted with EtOAc, washed (1.0N NaOH), dried(Na₂SO₄), filtered, and concentrated. The residue was dissolved indichloromethane (1.5 mL) and added to a mixture of EDCI (0.086 g, 0.45mmol), DMAP (0.007 g, 0.06 mmol), 5-(2-fluoro-phenyl)-oxazole carboxylicacid (0.087 g, 0.36 mmol) in dichloromethane (1.5 mL) under N₂. Thereaction was stirred for 65 h, diluted with dichloromethane, washed(1.0N HCl, 2.0N NaOH, H₂O, and brine), dried (MgSO₄), filtered, andconcentrated. Column chromatography (silica gel, acetone/dichloromethanegradient) gave the title compound (0.111 g, 81%). Mass Spectrum (FIA)(m/z) 456.2 [M+1].

Preparation 109N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-fluoro-3-iodophenyl)-5-methylisoxazol-4-yl]carboxamide

[0538] In a fashion similar to that described for preparation 108, acompound from preparation 105(0.1 g, 0.3 mmol), TFA (2 mL),dichloro-methane (1.5 mL), EDCI (0.086 g, 0.45 mmol), DMAP (0.007 g,0.06 mmol), 3-(2-fluoro-3-iodo-phenyl)-5-methyl-isoxazole-4-carboxylicacid (0.125 g, 0.36 mmol), and dichloromethane (1.5 mL) gave the titlecompound (0.104 g, 62%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 562.1[M+1].

Preparation 110N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-fluoro-3-iodophenyl)-5-iodophenylyl]carboxamide

[0539] In a fashion similar to that described for preparation 108, acompound from preparation 105 (0.1 g, 0.3 mmol), TFA (2 mL),dichloro-methane (1.5 mL), EDCI (0.125 g, 0.45 mmol), DMAP (0.007 g,0.06 mmol), 3-(2-fluoro-5-iodo-phenyl)-5-methyl-isoxazole-4-carboxylicacid (0.125 g, 0.36 mmol), and dichloromethane (1.5 mL) gave the titlecompound (0.088 g, 53%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 562.1[M+1].

Preparation 111N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2,4-difluorophenyl)-5-methylisoxazol-4-yl]carboxamide

[0540] In a fashion similar to that described for preparation 108, acompound from preparation 105 (0.1 g, 0.3 mmol), TFA (2 mL),dichloromethane (1.5 mL), EDCI (0.086 g, 0.45 mmol), DMA (0.007 g, 0.06mmol), 3-(2,4-difluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid(0.086 g, 0.36 mmol), and dichloromethane (1.5 mL) gave the titlecompound (0.123 g, 90%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 454.2[M+1].

Preparation 112N-{(1S,3R)-3-[(phenylcarbonylamino)methyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-hexylisoxazol-4-yl]carboxamide

[0541] In a fashion similar to that described for preparation 108, acompound from preparation 105 (0.1 g, 0.3 mmol), TFA (2 mL),dichloromethane (1.5 mL), EDCI (0.086 g, 0.45 mmol), DMAP (0.007 g, 0.06mmol), 3-(2-chloro-6-fluoro-phenyl)-5-hexyl-isoxazole-4-carboxylic acid(0.117 g, 0.36 mmol), and dichloromethane (1.5 mL) gave the titlecompound (0.112 g, 69%) after column chromatography (silica gel,acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 540.5[M+1].

Preparation 113 Phenylmethyl2-((3S,1R)-3-{[5-methyl-3-(6-fluoro-2-iodophenyl)isoxazol-4-yl]carbonylaminol}cyclohexyl)acetate

[0542] In a fashion similar to that described for preparation 99, acompound from preparation 45 (5.1 g, 14.7 mmol), dichloromethane (30mL), TFA (30 mL), dichloromethane (150 mL),3-(2-fluoro-6-iodo-phenyl)-5-methylisoxazole-4-carboxylic acid (6.39 g,17.49 mmol), and Et₃N (6.03 mL, 43.4 mmol) gave the title compound (7.15g, 86%) after column chromatography (silica gel, hexanes/EtOAcgradient). Mass Spectrum (ES+) (m/z) 577.0 [M+1].

Preparation 114 Phenylmethyl2-[(3S,1R)-3-(9-iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]acetate

[0543] A compound from Example 499 (1.87 g, 3.35 mmol), 1.0N NaOH (6.7mL, 6.7 mmol), and dioxane (20 mL) were allowed to react for 2 h at 50°C. in a fashion similar to that of preparation 29 to give the titlecompound (1.57 g, 100%). Mass Spectrum (ES+) (m/z) 467.0 [M+1.

Preparation 115 N-({(3S,1R)-3-aminocyclohexyl}methyl) benzamide

[0544] A solution of a compound from preparation 105 (5.3 g, 15.96 mmol)in TFA (50 mL) was stirred for 2 h. The reaction was concentrated usingbenzene azeotrope, diluted with EtOAc, washed (1.0N NaOH), dried(Na₂SO₄), filtered, and concentrated to give the title compound (3.41 g,92%). Mass Spectrum (S+) (m/z) 233.1 [M+1].

Preparation 116N-[(1S,3S)-3-(3-oxo-3-phenylpropyl)cyclohexyl][5-methyl-3-(6-fluoro-2-iodophenyl)isoxazolyl]carboxamide

[0545] To a solution of a compound from preparation 115 (3.4 g, 14.7mmol), Et₃N (6.14 mL, 44.1 mmol) in dichloromethane (150 mL) was added3-(2-fluoro-64-iodo-phenyl)₅-methylisoxazole-4-carboxylic acid (6.97 g,19.4 mmol) under N₂ and stirred for 4 h. The reaction was diluted withdichloromethane, washed (0.1N HCl then brine), dried (MgSO₄), filtered,and concentrated. Column chromatography (silica gel,acetone/dichloromethane gradient) gave the title compound (4.89 g, 59%).Mass Spectrum (ES+) (m/z) 562.0 [M+1].

Preparation 117 4-Amino-1-ethylcyclohexanecarboxylate hydrochloride

[0546] Thionyl chloride (2.55 mL, 35 mmol) was added dropwise toabsolute ethanol (100 mL) under a N₂ atmosphere. The resulting solutionwas stirred at room temperature for 10 min then4-amino-1-cyclohexanecarboxylic acid (4.29 g, 30 mmol, cis, transmixture) was added as a solid. The resulting solution was stirred atroom temperature overnight. The solvent was removed in vacuo, theresidue dissolved in ethanol (25 mL) and this solution was slowly addedto a flask containing rapidly stirred ether (700 mL). The precipitatethat formed was collected by filtration and dried in vacuo to give 5.75g, 92% as a white solid. MS (ion spray) 172 (M+1).

Preparation 118 Ethyl4-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexanecarboxylate

[0547] To a solution of a compound from preparation 117 (1.04 g, 5 mmol)in methylene chloride (15 mL) was added triethyl amine (0.8 mL, 5.7mmol) followed by3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (1.37g, 5 mmol) in methylene chloride (100 mL), and an additional aliquot oftriethyl amine (0.75 mL, 5.3 mmol). After an initial exotherm themixture was stirred at room temperature for 4 h. The mixture was dilutedwith methylene chloride, washed with water, 1N aqueous hydrochloric acidsolution, and brine, dried (MgSO₄), filtered, and concentrated in vacuo.The residue was purified by flash chromatography, eluting with 4:1toluene: ethyl acetate, to give 2.0 g 98% of the title compound as awhite solid. ¹H-NMR was consistent with the desired structure. MS (ionspray) 409.3 (M+1).

Preparation 119 Ethyl4-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylate

[0548] To a room temperature solution of a compound from preparation 118(1.75 g, 4.28 mmol) in anhydrous DMF (20 mL) was added potassiumr-butoxide (560 mg, 5 mmol). The resulting solution was stirred for 50min, at which time TLC (1:1 hexane:ethyl acetate) showed the startingmaterial had been consumed. The addition of 1N hydrochloric acidsolution (5 mL) and water (95 mL) quenched the reaction. The mixture wasextracted with ethyl acetate, the extracts were washed with water, andbrine, dried (MgSO₄), filtered, and concentrated in vacuo. The residuewas purified by flash chromatography, eluting with 9:1 methylenechloride: THF, to give 1.43 g 85% of the title compound, approximately2:1 mixture of diastereoisomers, as a yellow tinted solid. ¹H-NMR wasconsistent with the desired structure. MS (ion spray) 389 (4+1).

Preparation 1204-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylic acid

[0549] To a solution of a compound from preparation 119 (390 mg, 1 mmol)in THF (7 mL) was added 0.5 M LiOH solution (5 mL). The mixture wasstirred at room t temperature for 3 days then acidified with of 0.1Nhydrochloric acid solution (5 mL) and extracted with ethyl acetate. Theextracts were washed with brine, dried (MgSO₄), filtered, andconcentrated in vacuo to give 370 mg of the title compound as a yellowfoam. NMR was consistent with the desired product.

Preparation 121 (3-Aminocyclohexyl)(phenylsulfonyl)amine

[0550] A solution of 1,3-diaminocyclohexane (1.14 g, 10 mmol,undetermined isomer mixture) in methylene chloride (50 mL) was cooled to0° C. and phenylsulfonyl chloride (0.64 mL, 5 mmol) was added dropwise.The mixture was stifled at 0° C. for 4 h, then 1N sodium hydroxidesolution (10 mL) was added and the mixture stirred an additional 5 min.The phases were separated, the organic phase was dried (K₂CO₃),filtered, and concentrated in vacuo. Toluene was added and the mixturere-concentrated to remove any remaining diamine, to give 0.77 g of asemi solid. ¹H-NMR was consistent with the desired structure. MS (ionspray) 255 (M+1).

Preparation 122[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-N-{3-[(phenylsulfonyl)amino]cyclohexyl}carboxamide

[0551] To a solution of a compound from preparation 121 (750 mg, 2.95mmol theoretical) in methylene chloride (30 mL) was added triethylamine(0.6 mL, 4.3 mmol) followed by3-(2-chloro-6-fluoro-phenyl)5-methylisoxazole-4-carbonyl chloride (822mg, 3 mmol). The resulting mixture was stirred at room temperature for 3h. The mixture was diluted with ethyl acetate, washed with 1Nhydrochloric acid solution, saturated aqueous sodium bicarbonatesolution, brine, then dried (MgSO₄), filtered, and concentrated invacuo. Radial chromatography eluting with 95:5 methylene chloride: THFgave the less polar cis isomer (780 mg), mixed fractions (130 mg), andthe more polar trans isomer (410 mg). The cis isomer: ¹H-NMR wasconsistent with the desired structure, plus a small amount of thebis-sulfonylated diamine. MS (ion spray) 492 (M+1). For the transisomer. ¹H-NMR was consistent with the desired structure. MS (ion spray)492 (M+1).

Preparation 123 2-{(3S,1R)-3-[(t-Butoxy)carbonylamino]cyclohexyl}aceticacid

[0552] A compound from preparation 45 (3.30 g, 0.0095 mol) was combinedwith aqueous 2N sodium hydroxide (35 mL), tetrahydrofuran (10 mL), andethanol (10 mL) and the mixture stirred at room temperature for 2 h. Themixture was then concentrated in vacuo to remove volatile organics andadditional water was added to the aqueous mixture. This basic aqueousmixture was then extracted with diethylether followed by carefulacidification using 1N HCl. The acidic aqueous mixture was thenextracted with ethyl acetate. The combined ethyl acetate extracts weredried over sodium sulfate followed by concentration in vacuo whichprovided the title compound (2.40 g, 98%) as a white solid. MS(ES):(M−1)⁻ 256.2 m/z.

Preparation 124 N-[(1S,3R)-3-(2-Hydroxyethyl)cyclohexyl](t-butoxy)carboxamide

[0553] The compound from preparation 123 (2.10 g, 0.0082 mol) wasdissolved in dry THF (35 mL) and the mixture cooled in an ice bath undera nitrogen atmosphere. Then borane-tetrahydrofuran (1.0 M, 12.25 mL,0.0122 mol) was added via syringe and the mixture stirred overnightwhile slowly warming to room temperature. The reaction mixture wasquenched into ice water and solid NaCl was added. This mixture wasextracted with ethyl acetate and the combined extracts were dried oversodium sulfate and concentrated in vacuo. The resulting residue waschromatographed over silica gel using a CH₂Cl₂/THF mixture as eluantwhich allowed for isolation of 1.35 g (67%) of the desired alcohol.MS(ES): (M+1)+244.5 m/z.

Preparation 125N-[(1S,3R)-3-(2-p-toluenesulfonylethyl)cyclohexyl](t-butoxy)carboxamide

[0554] The compound from preparation 124 (1.30 g, 0.0054 mol) wascombined with p-toluenesulfonyl chloride (1.12 g, 0.0059 mol),triethylamine (1.49 mL, 0.011 mol) and DMAP (0.02 g, cat.) indichloromethane (30 mL) and the resultant mixture stirred overnight atroom temperature. The mixture was then concentrated in vacuo and theresidue chromatographed over silica gel using a mixture of CH₂Cl₂/THF aseluant which allowed for the isolation of the desired product (1.92 g,90%). MS(ES): (M+1)+398.2 M/Z.

Preparation 126N-{(1S,3R)-3-[2-(3-methylphenylthio)ethyl]cyclohexyl}(t-butoxy)carboxamide

[0555] 3-Methylthiophenol (0.15 mL, 0.0013 mol) was dissolved in DMF (10mL) at ambient temperature under a nitrogen atmosphere and sodiumhydride (60%, 0.050 g, 0.0013 mol) was added. After stirring for 15min., the compound from preparation 125 (0.50 g, 0.0013 mol) was addedand the mixture stirred overnight at ambient temperature. The mixturewas concentrated in vacuo and the residue chromatographed over silicagel using CH₂Cl₂/THF as eluant which allowed for isolation of 0.42 g(95%) of the desired product. MS(ES): (M+1)+350.5 m/z.

Preparation 127N-((1S,3R)-3-{2-[3-methylphenyl)sulfonyl]ethyl}cyclohexyl)(t-butoxy)carboxamide

[0556] The compound from preparation 126 (0.40 g, 0.00115 mol) wasdissolved in a methanol/acetone (10 mL)/(10 mL) mixture and NaHCO₃ (0.40g, 0.0048 mol) and water (5 mL) were added. Oxone® (1.46 g, 0.0024 mol)was then added and the mixture stirred at ambient temperature for 3.5 h.The mixture was concentrated in vacuo and the residue taken up inaqueous NaHCO₃ and extracted with CH₂Cl₂. The combined extracts weredried over sodium sulfate and concentrated in vacuo. The resultingresidue was chromatographed over silica gel using CH₂Cl₂/THF as eluantwhich allowed for isolation of 0.420 g (96%) of the desired sulfone.MS(FD): M+381.2, 382.2 m/z.

Preparation 128N-((1S,3R)-3-{2-[(3-methylphenyl)sulfonyl]ethyl}cyclohexyl)[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

[0557] The compound from preparation 127 (0.385 g, 0.0010 mol) and TFA(1.0 mL) were dissolved in CH₂Cl₂ (5.0 mL) and the mixture stirred atambient temperature for 2 h. The mixture was concentrated in vacuo andthe residue treated with aqueous NaHCO₃ and extracted with CH₂Cl₂. Thecombined extracts were dried over sodium sulfate and concentrated invacuo which allowed for recovery of crude amine. This amine was combinedwith 3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride(0.302 g, 0.0011 mol), triethylamine (0.31 mL, 0.0022 mol) and DMAP(0.010 g, cat.) in CH₂Cl₂ (6.0 mL) and the mixture stirred overnight atambient temperature. The mixture was concentrated in vacuo and theresulting residue chromatographed over silica gel using CH₂Cl₂/THF aseluant which allowed for isolation of 0.463 g (88%) of the desiredamide. MS(ES): (M+1)⁺ 519.2, 521.2 m/z.

Preparation 129N-[(1S,3R³-(2-phenylthioethyl)cyclohexyl](t-butoxy)carboxamide

[0558] Thiophenol (0.32 mL, 0.0031 mol) was combined with sodium hydride(60%, 0.15 g, 0.0038 mol) in DMF (15 mL) and a compound from preparation125 (1.25 g, 0.0031 mol) subsequently added in a manner similar topreparation 126. Workup and purification allowed for isolation of 1.0 g(98%) of the desired product. MS(ES): (M+1)⁺ 335.1 m/z.

Preparation 130N-[(1S,3R)-3-(2-phenylthioethyl)cyclohexyl][3-(2-chloro-6-fluorophenyl)-5-methyl]isoxazol-4-yl]carboxamide

[0559] The compound from preparation 129 (0.50 g, 0.0015 mol) wascombined with TFA (2 mL) in CH₂Cl₂ (10 mL) and treated in a mannersimilar to preparation 128. The resulting crude amine (0.213 g, 0.00097mol) was combined with3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride(0.27 g, 0.001097 mol) and triethylamine (0.27 mL, 0.0019 mol) in CH₂Cl₂(10 mL) again in a manner similar to preparation 128. Workup andpurification allowed for isolation of 0.413 g (58%) of the desiredamide. MS(ES): (M+1)⁺ 473.1, 475.1 m/z.

Preparation 131N-((1S,3R)-3-{2-[benzylsulfonyl]ethyl}cyclohexyl)(t-butoxy)carboxamide

[0560] Benzyl mercaptan (0.15 mL, 0.0013 mol) was combined with sodiumhydride (60%, 0.05 g, 0.0013 mol) in DMF (10 mL) and the compound frompreparation 125 (0.50 g, 0.0013 mol) subsequently added in a mannersimilar to preparation 126. Workup and purification allowed forisolation of 0.27 g (61%) of the desired sulfide. This compound (0.27 g,0.0008 mol) was dissolved in a methanol/acetone (5 mL)/(5 mL) mixtureand NaHCO₃ (0.27 g, 0.0032 mol) and water (5 mL) were added. Oxone®(0.98 g, 0.0016 mol) was then added and the mixture treated in a similarmanner to preparation 127. Workup and purification allowed for isolationof 0.092 g (30%) of desired sulfone intermediate. MS(ES): (M+1)+382.5m/z.

Preparation 132N-((1S,3R³-{2-[Benzylsulfonylaethyl}cyclohexyl[3-(2-chloro-6-fluorophenyl-5-methylisoxazol]4-yl]carboxamide

[0561] The compound from preparation 131 (0.090 g, 0.00024 mol) wascombined with TFA (1 mL) in CH₂Cl₂ (3 mL) and treated in a similarmanner to preparation 127. The resulting crude amine was combined with3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.067g, 0.00024 mol), triethylamine (4 drops), and DMAP (0.005 g, cat.) inCH₂Cl₂ (3 mL) again in a manner similar to preparation 126. Workup andpurification allowed for isolation of 0.10 g (79%) of the desired amide.MS(ES): (M+1)⁺ 519.2, 521.1 m/z.

Preparation 133N-{(1S,3R)-3-[2-(3-Fluorophenylthio)ethyl]cyclohexyl}(t-butoxy)carboxamide

[0562] 3-Fluorothiophenol (0.14 mL, 0.0013 mol) was combined with sodiumhydride (60%, 0.055 g, 0.0014 mol) in DMF (6 mL) and the compound frompreparation 125 (0.50 g, 0.0013 mol) subsequently added in a mannersimilar to preparation 126. Workup and purification allowed forisolation of 0.40 g (89%) of the desired product. MS(ES): (M+1)⁺ 354m/z.

Preparation 134N-((1S,3R)-3-{2-[(3-Fluorophenyl)sulfonyl]ethyl}cyclohexyl)(t-butoxy)carboxamide

[0563] The compound from preparation 133 (0.38 g, 0.0011 mol) wasdissolved in a methanol/acetone (10 mL)/(10 mL) mixture and NaHCO₃ (0.36g, 0.0043 mol) and water (5 mL) were added. Oxone®) (1.30 g, 0.0021 mol)was then added and the mixture treated in a manner similar topreparation 125. Workup and purification allowed for isolation of 0.40 g(98%) of the desired sulfone intermediate. MS(ES): (M+1)⁺ 386.3 m/z.

Preparation 135N-{(1S,3R)-3-[2-(3-Fluorophenylthioethyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

[0564] The compound from preparation 134 (0.030 g, 0.00078 mol) wascombined with TFA (1.5 mL) in CH₂Cl₂ (6 mL) and treated in a mannersimilar to preparation 126. The resulting crude amine was combined with3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.213g, 0.00078 mol), triethylamine (0.22 mL, 0.0016 mol) and DMAP (0.015 g,cat.) in CH₂Cl₂ (10 mL) again in a manner similar to preparation 126.Workup and purification allowed for isolation of 0.38 g (93%) of thedesired amide. MS(ES): (M+1)⁺ 523.1, 525.2 m/z.

Preparation 136N-{(1S,3R)-3-[2-(4-Fluorophenylthio)ethyl]cyclohexyl}(t-butoxy)carboxamide

[0565] 4-Fluorothiophenol (0.16 mL, 0.0015 mol) was combined with sodiumhydride (60%, 0.059 g, 0.0015 mol) in DMF (15 mL) and a compound frompreparation 125 (0.59 g, 0.0015 mol) subsequently added in a mannersimilar to preparation 133. Workup and purification allowed forisolation of 0.52 g (98%) of the desired product. MS(ES): (M+1)⁺ 353.6m/z.

Preparation 137N-((1S,3R)-3-{2-[(3-Fluorophenyl)sulfonyl]ethyl}cyclohexyl)(t-butoxy)carboxamide

[0566] A compound from preparation 136 (0.50 g, 0.0014 mol) wasdissolved in a methanol/acetone (10 mL)/(10 mL) mixture and NaHCO₃ (0.50g, 0.0060 mol) and water (8 mL) were added. Oxone® (1.83 g, 0.0030 mol)was then added and the mixture treated in a manner similar topreparation 125. Workup and purification allowed for isolation of 0.50 g(92%) of the desired sulfone intermediate. MS(ES): (M+Na)⁺ 408.1 m/z.

Preparation 138N-((1S,3R)-3-{2-[(4-Fluorophenyl)sulfonyl]ethyl}cyclohexyl)[3-(6-chloro-2-fluorophenyl)-5-methylisoxazolfyl]-carboxamide

[0567] The compound from preparation 137 (0.45 g, 0.0012 mol) wascombined with TFA (2 mL) in CH₂Cl₂ (10 mL) and treated in a mannersimilar to preparation 126. The resulting crude amine (0.30 g, 0.0011mol) was combined with 32-chlorofluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.29 g, 0.0011mol), triethylamine (0.29 mL, 0.0021 mol) and DMAP (0.010 g, cat.) inCH₂Cl₂ (20 mL) again in a manner similar to preparation 126. Workup andpurification allowed for isolation of 0.506 g (92%) of the desiredamide. MS(ES): (M+I) 523.1, 525.1 m/z.

Preparation 139 Diphenylmethyl2-((1R)-3-oxocyclohexyl)propane-1,3-dioate

[0568] To a flame dried flask at 0° C. was added lithium aluminumhydride (3.0 mL, 3.0 mmol, 1.0M in tetrahydrofuran) followed by(R)-(+1,1′-bi-2-napthol (1.71 g, 6.0 mmol) in anhydrous tetrahydrofuran(24 mL). After 30 min, the solution was allowed to warm to roomtemperature. A solution of sodium hydride (108 mg, 2.7 mmol, 60% inmineral oil) and dibenzylmalonate (675 μL, 2.7 mmol) in anhydroustetrahydrofuran (30 mL) was then added to the reaction dropwise overapproximately 2 min. To this mixture were then added 2-cyclohexen-1-one(2.91 mL, 30.0 mmol) and dibenzylmalonate (7.5 mL, 30 mmol), and thereaction was then stirred at room temperature, under a nitrogen atm,overnight. To the reaction was added 1N hydrochloric acid (60 mL, 60mmol, 1N in water), followed by extraction with ethyl acetate (3×200mL). The combined organic layers were then washed with saturated sodiumbicarbonate solution, dried over magnesium sulfate and concentrated.Purification by flash chromatography on silica gel (eluting with 5-7.5%acetone/hexane) gave 10.25 g of the title compound as a opaque solid,90% yield. ¹H NMR: consistent with structure. MS (ion spray) 381 (M⁺+1).

Preparation 140 cis-Diphenylmethyl2-(3-hydroxycyclohexyl)propane-1,3-dioate

[0569] To a solution of a compound from preparation 139 (6.13 g, 16.1mmol) in tetrahydrofuran (120 mL), methanol (10 mL), and water (10 mL)was added sodium borohydride (1.22 g, 32.2 mmol). After 10 min., thereaction was poured into 150 mL of a saturated ammonium chloridesolution, and extracted with ethyl acetate. The ethyl acetate layer waswashed with additional saturated ammonium chloride solution, saturatedsodium bicarbonate solution, dried over magnesium sulfate, andconcentrated. Purification by flash chromatography on silica gel(eluting with 5-13% acetone/hexane) gave 5.38 g of the title compound asa clear oil, 87% yield. ¹H NMR: consistent with structure. MS (ionspray) 383 (M⁺+1).

Preparation 141 cis-Phenylmethyl 2-(3-hydroxycyclohexyl)acetate

[0570] To a solution of a compound from preparation 140 (5.38 g, 14.07mmol) in anhydrous methylsulfoxide was added water (0.51 mL, 28.13 mmol)and lithium chloride (1.19 g, 28.13 mmol). The reaction was placed in anoil bath at 175° C. and stirred vigorously for 2.5 h. The reaction wasadded to water and extracted with ethyl acetate twice. The organic layerwas washed with water (×2), saturated sodium bicarbonate solution (×2),dried over magnesium sulfate and concentrated. Purification by flashchromatography on silica gel (eluting with 13% acetone/hexane) gave 1.81g of the title compound as a yellow oil, 52% yield. ¹H NMR: consistentwith structure.

Preparation 142 cis-Phenylmethyl 2-(3-azidocyclohexyl)acetate

[0571] To a solution of a compound from preparation 141 (1.81 g, 7.29mmol) in anhydrous toluene (70 mL) was added triphenylphosphine (3.82 g,14.58 mmol), Zn(N₃)₃.pyridine₂ (1.68 g, 5.47 mmol), followed by dropwiseaddition of diethyl azodicarboxylate (2.30 mL, 14.58 mmol) overapproximately 15 min., and the reaction was stirred at room temperatureovernight under a nitrogen atmosphere. Filtered through Celite® toremove zinc salts, dilute with ethyl acetate, wash with 0.1N sodiumhydroxide (×3), water, saturated sodium bicarbonate solution, dry overmagnesium sulfate and concentrated. Purification by flash chromatographyon silica gel (eluting with 3.5% ethyl acetate/hexane) gave 652 mg ofthe title compound as an oil, 33% yield. ¹H NMR: consistent withstructure.

Preparation 143 cis-Phenylmethyl2-{3-[(t-butoxy)carbonylamino]cyclohexyl}acetate

[0572] To a solution of a compound from preparation 142 (652 mg, 2.4mmol) and t-butoxycarbonyl anhydride (1.10 mL, 4.8 mmol) in ethylacetate (50 mL) under a nitrogen atmosphere was added Lindlar's catalyst(270 mg, 5% by weight). The mixture was subjected to a hydrogenatmosphere at room temperature overnight. The mixture was filtered overCelite® to remove the catalyst and concentrated. Purification by flashchromatography on silica gel (eluting with 15% ethyl acetate/hexane)gave 820 mg of the title compound as a clear oil, 100% yield.

[0573]¹H NMR: consistent with structure.

Preparation 144 cis-Phenylmethyl2-(3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)acetate

[0574] A solution of a compound from preparation 143 in trifluoroaceticacid was stirred at room temperature for 30 min. The solution wasconcentrated, followed by azeotropic removal of the remaining solventwith acetonitrile (×3). The crude product was dissolved in ethylacetate, washed with 1N sodium hydroxide (×2), dried over magnesiumsulfate and concentrated. To a solution of the resulting oil indichloromethane (20 mL) was added3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (748mg, 2.72 mmol), triethylamine (1.03 mL, 7.43 mmol), and dimethylaminopyridine (30 mg, 0.25 mmol), followed by triethylamine (1.03 mL, 7.43mmol) dropwise via syringe. The reaction was stirred overnight undernitrogen at room temperature. The solution was washed with 0.1N HCl(×3), water, saturated sodium bicarbonate solution, dried over magnesiumsulfate and concentrated. Purification by flash chromatography on silicagel (eluting with 0-30% ethyl acetate/hexane) gave 1.13 g of the tidecompound as a clear oil, 94% yield. ¹H NMR: consistent with structure.

Preparation 1452-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]aceticacid

[0575] To a solution of a compound from Example 494 (291 mg, 0.63 mmol)in dioxane (5 mL) was added 5N NaOH (5 mL) and the solution heated toreflux for 1 h. Upon cooling the reaction was quenched with 1Nhydrochloric acid, and extracted with 20% isopropanol/chloroform (×3),dried over magnesium sulfate and concentrated. The resulting brown oilwas treated with ethyl ether, sonicated, and a brown solid filtered out,to give 164 mg of the title compound, 70% yield. ¹H NMR: consistent withstructure.

Preparation 146trans-5-[3-(Aminomethyl)cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydrochloride

[0576] To trans-racemic[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]carbamicacid t-butyl ester (1.22 g, 2.74 mmol) was added acetic acid saturatedwith HCl_((g)) (30 mL, ˜3N in HCl) and the solution stirred vigorouslyat room temperature for 10 min. The reaction was concentrated, followedby addition of acetonitrile and concentrated to assist in the removal ofacetic acid. The resulting white solid was treated with ethyl ether,sonicated, and filtered to yield 985 mg of the title compound as a whitesolid, 94% yield. ¹H NMR: consistent with structure. MS (ion spray) 346(M⁺+1).

Preparation 147 2-Fluoro-3-iodobenzaldehyde

[0577] To a solution of diisopropylamine (10.42 mL, 74.36) in THF (135mL) under N₂ in an ice bath at 0-5° C. was added dropwise over 10 minn-BuLi (42.25 mL, 67.6 mmol) and stirred at this temperature for 10 min.Cooled the reaction mixture to −78° C. in a dry ice/acetone bath anddropwise added 1-fluoro-2-iodobenzene (7.88 mL, 67.6 mmol) over 5 min.Stirred at this temperature for 1 h, dropwise added DMF (6.26 mL, 74.36mL) over 5 min, and stirred for 10 min. Added Acetic Acid (13.5 mL)followed by H₂O and extracted with Et₂O (2×). The combined organicsolution was washed (0.1 N HCl then brine), dried (MgSO₄), filtered andconcentrated. The crude benzaldehyde (16.9 g) was taken onto the nextstep without purification. ¹H NMR was consistent with structure.

Preparation 148 2-Fluoro-3-iodobenzaldoxime

[0578] To a mixture of a compound from preparation 147 (16.9 g, 67.6mmol) in H₂O (35 mL), EtOH (35 mL), and ice (25 g) was addedhydroxylamine hydrochloride (4.8 g, 74.4 mmol). Then, 169 mmol of 50%NaOH (6.76 g in 6.76 mL H₂O) was added with stirring. Enough ice to keepthe temperature at 25-30° C. was added. Stirred for 2.5 h, acidifiedwith conc. HCl to pH 4 (ice was added to keep the temperature at 25-30°C.), and extracted with Et₂O (2×). The combined organic solution waswashed (brine), dried (MgSO₄), filtered, and concentrated. The residuewas chromatographed on silica gel (EtOAc/dichloromethane gradient) togive the title compound (8.02 g, 45% over 2 steps). Mass Spectrum (FIA)(m/z) 264.0 [M−1].

Preparation 149 2-Fluoro-3-iodobenzohydroximinoyl chloride

[0579] To a stirred solution of a compound from preparation 148 (8.02 g,30.2 mmol) in DMF (45 mL) at 25-30° C. was added about 1/5 of 30.2 mmol(4.03 g) of NCS. The initial NCS addition results in a slighttemperature decrease. If the reaction does not self-initiate within 10min., as indicated by a slight temperature rise, 5 pipettes of gas fromthe headspace of a conc. HCl reagent bottle was bubbled into the DMFsolution. Carefully added rest of NCS and temperature rose to 45-55° C.Once reaction cooled to r.t. (about 1 h), added ice H₂O and extractedwith Et₂O (2×). The combined organic solution was washed with (brine),dried (MgSO₄), filtered, and concentrated. The title compound (9.04 g)was taken on to the next step without purification. ¹H NMR wasconsistent with structure.

Preparation 150 Ethyl3-(6-fluoro-2-iodophenyl)-5-methylisoxazole-4-carboxylate

[0580] To a solution of a compound from preparation 149 (30.2 mmol) andethyl-2-butynoate (4.23 mL, 36.24 mmol) in Et₂O (120 mL) under N₂stirring at 05° C. was added dropwise a solution of Et₃N (5.46 mL, 39.26mmol) in Et₂O (17 mL) over 1 h. Allowed to warm to room temperature andstirred overnight. Added Et₂O and washed (H₂O then brine), dried(MgSO₄), filtered, and concentrated. The crude residue waschromatographed on silica gel (dichloromethane) to give the tidecompound (6.92 g, 61%). Mass Spectrum (FIA) (m/z) 376.15 [M+1].

Preparation 153 N-t-Butyl-N′-(2-chloro-6-fluorobenzylidene)hydrazinehydrochloride

[0581] A mixture of t-butyl hydrazine hydrochloride (1.24 g, 10 mmol)and 2-chloro-6-fluorobenzaldehyde (1.1 mL, 10 mmol) dissolved in aceticacid (5 mL) was stirred at 50° C. for half hour. Hexanes (10 mL) wasadded, filtered and washed the white solid with hexanes (20 mL). Yield:61%. ESMS: 229 (M+1).

Preparation 156 3-Methyl-5-(2-chloro-6-fluorophenyl)₄isoxazolecarboxylic acid ethyl ester

[0582] To a solution of ethyl 3-aminomethyl crotonate (4.79 g, 33.5mmol) in toluene (10 mL), was added triethylamine (3.73 g, 37 mmol). Thesolution was chilled using an ice bath, and then2-chloro-6-fluorobenzoyl chloride (6.47 g, 33.5 mmol) was added dropwiseover a 20 min period. The reaction was allowed to warm slowly to r.t.and stirred for 24 hr. The resulting suspension was then filtered, andthe filtrate diluted with ethyl acetate (100 mL) and transferred to aseparatory funnel. The organic layer was sequentially washed with water,brine, dried (sodium sulfate), and the volatiles removed under reducedpressure to provide the tide compound (9.46 g) as a golden solid, andprimarily one geometrical isomer. MS (ES) m/z 299.9 (M+H)⁺.

[0583] The crude adduct was then redissolved in glacial HOAc (50 mL) towhich was added NH₂OH.HCl (1.8 g, 1.1 eq). The solution was then heatedto reflux for 40-45 min to effect isoxazole formation. The reactionmixture was concentrated to an oil, diluted with ether, and transferredto a sep. funnel. The organic phase was washed with saturatedbicarbonate, brine, then dried. Filtration and concentration affordedcrude isoxazole ethyl ester (7.5 g), which was used without furtherpurification. MS (+ES) m/z 283.9 (M+H)⁺.

Preparation 1575-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylic acid

[0584] Hydrolysis of the ethyl ester was accomplished by dissolving thecrude ester (7.5 g, approx. 0.027 mol) in THF (250 mL), and adding aq.LiOH (1.344 g in 100 mL, 2 eq). After stirring overnight at r.t., thesolution was concentrated to ⅔^(rd) volume, diluted with EtOAc (200 mL)and 50 mL water, transferred to a separatory funnel, and the aqueousphase collected. The organic phase was washed twice, and the combinedaqueous phase was then acidified with 5N HCl. Back extraction with threewashings of EtOAc was then followed with a brine wash of the combinedorganics. After drying over Na₂SO₄, filtration and concentration, cleanisoxazole acid was obtained (2.94 g). NMR (CDCl₃) δ 7.13, 7.32 7.46 (3m,3H), 2.58 (s, CH₃). MS (−ES) m/z 253.8, 255.8 (M−H)⁻.

Preparation 1582-(3-{[5-(2-chloro-6-fluorophenyl)-3-methylisoxazol-4-yl]carbonylamino}cyclohexyl)-N-(3,4,5-trimethoxyphenyl)acetamide

[0585] To a compound from preparation 157 (60 mg, 0.234 mmol) in benzene(4 mL) containing catalytic amount of pyridine (20 μl) was added oxalylchloride (23 mL). After heating to reflux for 1 hr, an aliquot wasconcentrated under vacuum and analyzed by 1H-NMR (CDCl₃) for completionof acid chloride formation; ¹H-NMR (CDCl₃) 7.53 (d of t, 1H), 7.37 (d,1H), 7.17 (t,1H). (racemic)

[0586] Solvent was removed under vacuum. To a solution ofd,l-cis-1-amino 3-(N-3,4,5-trimethoxyphenyl)cyclohexyl-acetamide (60 mg,0.185 mmol) in dry MeCl₂ (4 mL) containing catalytic DMAP (10%) andpyridine (20 μl, 0.24 mmol) was added the crude acid chloride in 0.5 mLMeCl₂ at r.t. Reaction was allowed to proceed for 4 hr at which timeamide formation was complete by TLC. The reaction was diluted with MeCl₂and transferred to a sep funnel, washed with dil. HCl (pH 1), and theaqueous fraction was separated and reextracted two more times in thesame manner. The combined organics were then washed sequentially withsat'd bicarbonate, brine, dried over Na₂SO₄, filtered and concentratedunder vacuum to afford crude product (69 mg). Purification wasaccomplished via prep TLC (Chromatotron®, 1 mm SI plate) using 70%-90%EtOAc in hexane to obtain 24 mg (24% from amine). MS (+ES) m/z 559.9(M+H), 576.9 (M+NH₃).

Preparation 159(3-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazolecarbonyl]amino}cyclohexyl)aceticacid ethyl ester (cis)

[0587] A compound from preparation 157 (254 mg, 1 mmol) was dissolved inDMF (15 mL). EDC.HCl (211 mg, 1.1 eq) was then added, followed by DMAP(10 mg), and then cis-1,3-1(S)aminocyclohexyl-3(R)-acetic acid, methylester (60% ee, 188 mg, 1.1 eq) at r.t. After 18 hr, starting materialwas not yet fully consumed (TLC, NMR of aliquot), so the mixture washeated to 800 for 2 hr. The reaction was then cooled to r.t., anddiluted with EtOAc and 0.1 N HCl. The aqueous phase was reextractedtwice, and the combined organics washed with sat'd bicarbonate, brine,dried over Na₂SO₄. Filtration and concentration afforded crude product(207 mg). Purification using a Bond-Elut SI column (10 g, 4:3 hex/EtOAc)provided 34 mg (8%) of the title compound. MS (+ES) 411.0 (M+H)⁺.

Preparation 160 (3-{[5-(2Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexylmethyl)carbamicacid t-butyl ester

[0588] Using the acid chloride method described for preparation 158, 3mmol (0.689 g) of a cis/trans mixture of 1-amino, 3-Boc-aminomethylenecyclohexane was dissolved in CH₂Cl₂ (10 mL), followed by addition ofEt₃N (0.415 mL, 6 mmol), DMAP (cat, 20 mg), at rt. The above isoxazoleacid chloride of preparation 157 (3 mmol in 10 mL CH₂Cl₂) was then addeddropwise over 10 min. Reaction was allowed to proceed overnight. Thereaction mixture was then transferred to a sep funnel, diluted withadditional CH₂Cl₂, and washed sequentially with 5% citric acid (aq, pH34), sat'd bicarbonate, brine, then dried. Filtration and concentrationyielded crude product (brown oil). Purification by filtration through apad of Silica Gel 60 in a 60 mL sintered glass funnel using 2:1hexane/EtOAc afforded clean cis/trans product (0.830 g, 59% overall).NMR (CDCl₃) δ 7.2-7.6 (3 m,3H), 5.55 and 5.2 (trans/cis amide NH's), 4.5and 4.2 (cis/trans Boc NH's), 3.8 and 2.95 (trans/cis aminomethine(CH)), 2.58 and 2.55 (trans/cis CH₃), 0.6-2.9 (m's), 1.4 (2s, cis/transt-butyl). MS (+ES); 465.9 (M+H)⁺; (−ES); 463.9 (M−H)⁻, 499.9 (M+Cl−H)⁻,524 (M+Oac−H)⁻.

Preparation 161 (cis-3(S)-Aminocyclohexylmethyl)carbamic acid benzylester

[0589] S-amino enantiomer ofN-({3-[(t-butoxy)carbonyl-amino]cyclohexyl}methyl)(phenylmethoxy)carboxamide (1.0 g, 2.76 mmol) was treated with TFA (5mL) under N₂. After 20 min of stirring at r.t. the reaction wascomplete. The crude was then concentrated to an oil which was purifiedon a Varian Bond-Elut SCX column (10 g). The column was elutedconsecutively with CHCl₃, MeOH, and ammonia (2.0M in MeOH). The pureproduct was recovered from the ammonia fractions. The solvent wasremoved in vacuo to afford 0.632 g (87%) as a colorless oil. MS (ES+)m/z 263.0 (M+H)⁺.

Preparation 162(3-[{5-(2-Chloro-6-fluorophenyl)₃-methylisoxazole-4-carbonyl]amino}cyclohexylmethyl)carbamicacid benzyl ester

[0590] A solution from preparation 157 (1.0 g, 3.9 mmol) in toluene (30mL) was treated with a catalytic amount of pyridine (0.1 mL) and cooledto 0° C. The solution was then treated with oxalyl chloride (0.545 g,4.3 mmol) and stirred at r.t. for 2 hr.

[0591] 1H NMR showed the completion of the acid chloride formation; 7.52(d, 1H), 7.37 (d, 1H), 7.15 (t, 1H) The solvent was removed in vacuo. Asolution from preparation 161 (0.550 g, 2.09 mmol) and triethylamine(0.422 g, 4.18 mmol) in dry DMF (25 mL) was stirred at r.t. Thissolution was then treated with the acid chloride from preparation158(0.859 g, 3.135 mmol) which was added dropwise over two min. Thereaction was then catalyzed with DMAP (0.025 g, 0.21 mmol) and allowedto stir o.n. The reaction was diluted in EtOAc (250 mL), transferred toa sep funnel, and washed with a 5% citric acid solution (5×50 mL), sat.sodium bicarbonate solution (2×50 mL), brine (2×50 mL) and was driedover sodium sulfate. The EtOAc solution was filtered and the solventremoved in vacuo to yield an orange solid. The solid was purified usingsilica gel column chromatography. The column was prepared with CHCl₃ andthe product was eluted with 10% EtOAc in CHCl₃. The solvent was removedin vacuo to afford 0.584 g (56%) of the title compound as a white solid.MS (ES+) m/z 500.1 (M+H)⁺.

Preparation 163 cis-Octahydroquinolin-2-one

[0592] To a solution of 2-nitrocinnamic acid in 120 mL of acetic acid ina Parr shaker, was added PtO₂ (10 g). Hydrogen (3 atm) was thenintroduced, and the contents of the shaker were heated to 60° C. for 24b. After the mixture was cooled to r.t. and filtered through Celite®,the solvent was removed in vacuo, and the residue was dissolved inEtOAc, and transferred to a sep. funnel. Treatment with sat'd HCO₃—,brine, and then drying over Na₂SO₄, filtration and concentrationafforded predominantly cis lactam (<7% trans by NMR) in 55% yield (6 g).MS (+ES) m/z 254 (M+1)⁺.

Preparation 164 trans-Octahydroquinolin-2-one

[0593] To a solution of 3,4,5,6,7,8-hexahydro-1H-quinoline-2-one (0.1 g,0.66 mmol) in dioxane (10 mL) containing a catalytic quantity (40 μL)was added NaCNBH₃ (0.67 g). The reduction was left to stir for 20 hrs atr.t., and then diluted with EtOAc. The organic phase was treated withdilute HCl (3×), and the combined organics were washed with saturatedHCO₃—, brine, dried over Na₂SO₄, filtered and concentrated to afford themainly trans product (98 mg, 95%, 15-20% cis isomer). MS (+ES) m/z 254(M+1)⁺.

Preparation 165cis-3-(2-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexyl)propionicacid methyl ester

[0594] The acid chloride (0.4 mmol) of preparation 157 was prepared asdescribed previously, and added to a MeCl₂ solution (10 mL) of methyl3-((1S,2S)-2-aminocyclohexyl)propanoate (222 mg, 1.2 eq) followed byEt₃N (133 μl, 0.96 mmol) and DMAP (10%) at r.t. Acylation was allowed toproceed for 18 hr. Crude product was obtained by dilution of thereaction mixture with MeCl₂ and 0.1 N HCl, transferring to a sep funnel.The organic phase was then washed with sat'd bicarbonate, brine, thendried over Na₂SO₄. Filtration and concentration provided crude product,which was then purified using a Bond-Elut Si column (1 g, 1:1 hex/EtOAc)to generate pure methyl ester, (86 mg, 51%). MS (+ES) m/z 422.9/424.9(M+H).

Preparation 166cis-3-(2-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carbonyl]amino}cyclohexyl)propionicacid

[0595] To a solution of a compound from preparation 165 (86 mg, 0.2mmol) in THF (5 mL) was added 2 mL 0.5M aq. LiOH (5 eq), dropwise atr.t. Hydrolysis was complete at 2.5 hr. After dilution with water andEtOAc, the contents were transferred to a sep funnel, where addition ofenough 1N HCl was added to maintain pH 2. The aqueous phase was backextracted 3 times with additional solvent, and the combined organicswere then washed with brine, dried over Na₂SO₄. Filtration andconcentration afforded clean acid, 80 mg (97%), which was used withoutfurther purification. MS (+ES) m/z 408.9/410.9 (M+M).

Preparation 1675-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylicacid-{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]cyclohexyl}amide

[0596] To a compound from preparation 166 (40 mg, 0.1 mmol) in DMF (2mL) was added catalytic amount of DMAP (10%, 1 mg), followed by EDC.HCl(20.6 mg, 0.11 mmol) and 3,4,5-trimethoxyaniline (20.1 mg, 0.11 mmol) atr.t. After 18 hr, the reaction was transferred to a sep funnel anddiluted with EtOAc and 1N NaOH (aq. pH 9-10). The aqueous phase wasextracted 3 times, and combined EtOAc fractions were then washedsequentially with 1 N HCl, sat'd bicarbonate, brine, and then dried overNa₂SO₄. After filtration and concentration, crude amide was obtained (33mg). Starting material (7 mg) was also recovered from the aqueousfraction upon acidification and standard workup. The crude product wasthen chromatographically purified (Bond-Elut Silica column, 1 g, 2:1EtOAc/hexanes) to afford clean amide (48 mg, 50%). MS (ES+) 573.9, 575.9(M+H)⁺.

Preparation 168trans-3-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}cyclohexyl)propionicacid

[0597] A solution of methyl3-(2-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-yl]carbonylamino}cyclohexyl)propanoate(0.127 g, 0.3 mmol) in THF (5 mL) was treated with a 0.5 M sol'n of LiOHin water (3 mL). The sol'n was stirred at r.t. for 5 hr. The reactionwas diluted with water (3 mL) and washed with EtOAc (2×5 mL). The pH ofthe aqueous was adjusted to −3 with 0.1 M HCl and extracted with EtOAc(4×5 mL). The organic extractions were then washed with brine (2×5 mL),dried over sodium sulfate and the solvent removed to afford 0.095 g(80%) as a white solid. MS (ES+) m/z 409.0 (M+H)⁺, (ES−) m/z 407.0(M−H)⁻.

Preparation 169trans-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]cyclohexyl}amide

[0598] A sol'n of a compound from preparation 168 (0.095 g, 0.23 mmol)and EDC (0.115 g, 0.6 mmol) in DMF (25 mL) was treated with3,4,5-trimethoxyaniline (0.11 g, 0.6 mmol). A catalytic amount of DMAP(4 mg, 0.03 mmol) was also added The reaction mixture was stirred atr.t. overnight. The reaction was diluted in EtOAc (100 mL) and washedwith 5% citric acid sol (3×50 mL), water (2×50 mL), and dried oversodium sulfate. The solvent was removed in vacuo to afford a crude brownoil which was purified by a Varian Bond Elut SI column (10 g) with aneluting solvent of 1:1 Hexanes: EtOAc. The solvent was removed in vacuoto afford 0.072 g (54%) as an off white solid. MS (ES+) m/z 574.0(M+M)⁺, (ES−) m/z 572.1 (M−H)⁻, 632.1 (M+CH₃COO⁻)⁻.

Preparation 170{(3S,1R)-3-[(t-butoxy)carbonylamino]cyclopentyl}-N-benzylcarboxamide

[0599] A mixture of N-BOC-1R,3S-1 amino cyclopentane-3-carboxylic acid(229 mg, 1 mmol), EDC (286 mg, 1.5 mmol), benzyl amine (160 mg, 1.5mmol) and DMAP (5 mg, catalytic) dissolved in DMF (20 mL) was stirredovernight at rt. The reaction mixture was diluted with ethyl acetate(200 mL) and washed with 0.2M HCl (2×50 mL), water (2×50 mL), brine(2×50 mL), dried over Na₂SO₄, filtered, and evaporated to yield a whitesolid (160 mg, 50%). ESMS: 319 (M+1)⁺.

Preparation 171 (1R,3S)-1-Amino-M-phenylmethylcyclopentane-3-carboxamide

[0600] A compound from preparation 170 (100 mg, 0.31 mmol) was dissolvedin TFA reagent (9.25 mL TFA, 0.25 mL anisole, 0.25 mL TIS, 0.25 mLwater) and stirred at r.t for 30 m. TFA reagent was evaporated and theresidue was dissolved in chloroform (10 mL) and filtered through SCXcolumn and eluted with ammonia (10 mL, 2 M solution in methanol) andevaporated to yield title compound (68 mg, quantitative). ESMS: 219(M+1)⁺, 277 (M+Ac)⁺.

Preparation 172{(3S,1R)-3-[N-benzylcarbamoyl]cyclopentyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carboxamide

[0601] A compound from preparation 171 was dissolved in D; (25 mL) and2-chloro-6-fluorophenyl isoxazoyl chloride, triethylamine and DMAP wereadded and stirred overnight at r.t. The reaction mixture was dilutedwith ethyl acetate (100 mL) and washed with HCl (1M, 2×50 mL), water(2×50 mL), brine (2×50 mL), dried over sodium sulfate, filtered, andevaporated to yield title compound (248 mg, 80%, crude). ESMS: 456 (M)⁺.

Preparation 173 (3S,1R)(3-Hydroxymethylcyclopentyl)carbamic acid t-butylester

[0602] (1R,3S3-t-Butoxycarbonylaminocyclopentanecarboxylic acid (229 mg,1 mmol) was dissolved in THE (10 mL) and borane-THF (1.5 mL, 1Msolution) was added drop-wise at 0° C. and stirred overnight at r.t. Thereaction mixture was poured into ice-cold water (10 mL) and extractedwith ethyl acetate (2×50 mL). The ethyl acetate extract was washed withbrine, dried over sodium sulfate, filtered and evaporated to yield asemi solid (160 mg, 74%). ESMS (+): 216 (M+1)⁺, 250 (M+Cl)⁺.

Preparation 174 (3R,1S)-Toluenesulfonic acid3-t-butoxycarbonylaminocyclopentylmethyl ester

[0603] A compound from preparation 173 (150 mg, 0.69 mmol) was dissolvedin methylene chloride (20 mL) and p-toluenesulfonyl chloride (131 mg,0.69 mmol), triethylamine (268 μL, 1.86 mmol) and DMAP (10 mg) wereadded and stirred overnight. The methylene chloride solution was washedwith 1M HCl (2×10 mL), water (2×10 mL), brine (2×10 mL), dried oversodium sulfate, filtered and evaporated to yield the title compound (223mg, 86%). ESMS: 370 (M+1)⁺, M+Ac)⁺.

Preparation 175 (1R,3S)(3-Azidomethyl-cyclopentyl)-carbamic acid t-butylester

[0604] To a solution of a compound of preparation 174 (96 mg, 0.26 mmol)dissolved in DMF (10 mL) sodium azide was added and stirred at 80° C.overnight The reaction mixture was diluted with ethyl acetate (50 mL)and washed with water (2×25 mL), brine (2×25 mL), dried over sodiumsulfate, filtered and evaporated to yield the title compound (55 mg, 88%crude). ¹HNMR (CDCl₃): 1.00-1.12 (m, 1H), 1.2-1.50 (m, 2H), 1.40 (s,9H), 1.52-1.70 (m, 1H), 1.71 (1.82 (m, 1H), 1.89-2.00 (m, 1H), 2.10-2.30(m, 2H), 3.26-3.28 (d, 2H), 4.80 (br S, 1H).

Preparation 176 (1R,3S)(3-Aminomethylcyclopentyl)carbamic acid t-butylester

[0605] To a solution of a compound from preparation 175 (55 mg, 0.23mmol) dissolved in methanol (10 mL) palladium/C (10 mg, 10%) was addedand stirred under hydrogen (balloon) at for 2 h at rt. The solution wasfiltered off through Celite® and evaporated to yield a white solid (44mg, 89%). ESMS: 215 (M+1)⁺.

Preparation 177 (1R,3S)-[3-(Benzoylaminomethyl)cyclopentyl]carbamic acidt-butyl ester

[0606] To a solution of a compound from preparation 176 (44 mg, 0.2mmol) dissolved in DMF (10 mL), benzoyl chloride (35 mg, 0.25 mmol),triethylamine (0.5 mL) and DMAP (5 mg) was added and stirred overnightat rt. The reaction mixture was diluted with ethyl acetate (50 mL),washed with 1M HCl (2×20 mL), water (2×20 mL), brine (2×20 mL), driedover sodium sulfate, filtered and evaporated to get title compound (70mg, crude quantitative). ESMS: 319 (M+1)⁺, 317 (M−1)⁻, 353 (M+Cl)⁻, 317(M+Ac)⁻.

Preparation 178 (1R,3S)-N-(3-Aminocyclopentylmethyl)benzamide

[0607] A compound from preparation 177 (70 mg, 0.22 mmol) was dissolvedin TFA (5 mL) and stirred for 1/2 h at rt. TFA was evaporated undervacuum and the residue was dissolved in chloroform (5 mL) passed throughSCX column (Varian Bond Elut, 6 cc) and a eluted with 2M ammonia(methanol) to obtain title compound (34 mg, 72%). ESMS: 219 (M+1)⁺, 277(M+Ac)⁻.

Preparation 179(1R,3S)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid[3-(benzoylaminomethyl)cyclopentyl]amide

[0608] To a solution of a compound from preparation 178 (34 mg, 0.15mmol) in DMF (5 mL), 2-chloro-6-fluorophenyl isoxazoyl chloride (85 mg,0.3 mmol), triethylamine (1 mL), DMAP (5 mg) were added and stirredovernight. The reaction mixture was diluted with ethyl acetate (50 mL),washed with 1M HCl (2×20 mL), water (2×25 mL), brine (2×20 mL), driedover sodium sulfate, filtered, evaporated and chromatographed (silicagel, 50% ethyl acetate in hexanes) to yield title compound (36 mg, 52%).ESMS: 456 (M)⁺, 514 (M+Ac)⁻.

Preparation 180 (1S,4R)(4-Hydroxymethyl-cyclopent-2-enyl)carbamic acidt-butyl ester

[0609] To a solution of 4-t-butoxycarbonylaminocyclopent-2-enecarboxylicacid (1 g, 4.4 mmol) dissolved in THF (100 ml) and added with borane-THF(4.5 ml, 4.5 mmol) at 0° C. and stirred overnight at r.t. The reactionmixture was poured into ice-cold water (100 ml) and extracted with ethylacetate. The ethyl acetate extract was washed with brine, dried oversodium sulfate and evaporated to obtain the tide compound (655 mg, 69%).ESMS: 214 (M+1)⁺, 236 (M+23)⁺, 248 (M+35)⁻, 272 (M+59)⁻.

Preparation 181 (1S,4R)-Toluene-4-sulfonic acid4-t-butoxycarbonylamino-cyclopent-2-enylmethyl ester

[0610] A solution of a compound from preparation 180 (655 mg, 3 mmol),p-tosyl chloride (760 mg, 4 mmol), triethyl amine (0.4 ml) and DMAP (100mg) dissolved in dichloromethane (50 ml) was stirred at rt, overnight.The reaction mixture was washed with dilute hydrochloric acid (2×),water (2×), brine (2×), dried over sodium sulfate and evaporated toobtain the title compound (1.0 g, 90%). ESMS: 368 (M+1)⁺, 426 (M+59)⁻.

Preparation 182 (1S,4R)(4-Azidomethylcyclopent-2-enyl)carbamic acidt-butyl ester

[0611] To a solution of a compound from preparation 181 (1 g, 2.7 mmol)in DMF (50 mL), sodium azide (200 mg, 3 mmol) was added and stirred at80° C. overnight. The reaction mixture was diluted with ethyl acetate(100 mL) and washed with water (2×50 mL), brine (2×50 mL), dried oversodium sulfate and evaporated to yield the title compound(quantitative). IR (chloroform): 2096.6 cm⁻ (azide). ¹HNMR (CDCl₃): δ1.27-1.30 (m, 2H), 1.43 (s, 9H), 2.51-2.56 (m, 2H), 3.27-3.35 (m, 2H),5.76 (s, 2H).

Preparation 183 (1S,3R)-(3-Aminomethylcyclopentyl)carbamic acid t-butylester

[0612] To a solution of a compound from preparation 182 (300 mg, 1.25mmol) in methanol (10 mL), Pd/C (10%, 50 mg) was added and the reactionmixture was hydrogenated (1 atm) overnight at rt. The reaction mixturewas filtered through celite and evaporated to yield the title compound(222 mg, 89% o). ESMS: 215 (M+1)⁺.

Preparation 184 (1S,3R)[3-(Benzoylaminomethyl)cyclopentyl]carbamic acidt-butyl ester

[0613] A mixture of a compound from preparation 183 (222 mg, 1.03 mmol),benzoyl chloride (210 mg, 1.5 mmol), triethylamine (1 mL), and DMAP (10mg, catalytic) in DMF (50 mL) was stirred overnight The reaction mixturewas diluted with ethyl acetate (100 mL) and washed with dilutehydrochloric acid (1M, 2×50 mL), water (2×50 mL), brine (2×50 mL), driedover sodium sulfate, filtered and evaporated to yield the title compound(395 mg). ESMS: 319 (M+1)⁺, 377 (M+59)⁻.

Preparation 185 (1S,3R)-N-(3-Aminocyclopentylmethyl)benzamide

[0614] A compound from preparation 184 (crude 390 mg) was dissolved intrifluoroacetic acid (10 mL) and stirred for half an hour at rt. Thereaction mixture was evaporated and chromatographed (Varian Bond Elut 60cc, SCX column, 2M ammonia solution in methanol) to obtain the titlecompound (233 mg, 87%). ESMS: 219 (M+1)⁺.

Preparation 186(1S,3R)-3-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylic acid[3-(benzoylaminomethyl)cyclopentyl]amide

[0615] A mixture of a compound from preparation 185 (230 mg, 1.05 mmol),3-(2-chloro, 6-fluorophenyl)-5-methyl-4-isoxazoyl chloride (328 mg, 1.2mmol), triethyl amine (1 mL), dimethyl amino pyridine (DMAP, 50 mg)dissolved in DMF (20 mL) was stirred overnight at rt. The reactionmixture was diluted with ethyl acetate (100 mL) and washed with diluteHCl (1M, 2×50 mL), water (2×50 mL), brine (2×50 mL), dried over sodiumsulfate, filtered, evaporated and then chromatographed (Varian BondElut, Si, 60 cc, 50% EtOAc in Hexane) to obtain the title compound (100mg, 20%). ESMS: 456 (M)⁺, 515 (M+59)⁻.

Preparation 187(1S,3R){3-[(4-Fluorobenzoylamino)methyl]cyclopentyl}carbamic acidt-butyl ester

[0616] To a solution of a compound from preparation 183 (68 mg, 0.31mmol) and 4 fluorobenzoylchloride (60 mg, 0.38 mmol) dissolved in DMF (2mL), triethyl amine (0.5 mL) and DMAP (10 mg) were added and stirred forfour hours at rt. The reaction mixture as diluted with ethyl acetate (20mL) and washed with dilute hydrochloric acid (2×20 L, 0.1 M), water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered andvaporated to obtain 492323 (127 mg). ESMS: 337 (M+1)⁺, 395 (M+59)⁻.

Preparation 188 (1S,3R)(3-Aminocyclopentylmethyl)fluorobenzamide

[0617] A compound from preparation 187 (127 mg) was dissolved intrifluoroacetic acid (2 mL) and stirred for half an hour at rt. Thereaction mixture was evaporated under vacuum and the residue wasdissolved in methylene chloride, filtered through SCX column (Bond Elut,60 cc) and eluted with ammonia (2M in methanol) to obtain the titlecompound (81 mg, 91%). ESMS: 237 (M+1)⁺, 295 (M+59)⁻.

Preparation 189(1R,3S)-3-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylic acid{3-[(4-fluorobenzoylamino)methyl]cyclopentyl}amide

[0618] A solution of a compound from preparation 188 (81 mg, 0.34 mmol),chloro fluoro phenyl isoxazoyl chloride (113 mg, 0.41 mmol), triethylamine (0.5 mL) and DMAP (10 mg) in DMF (5 mL) was stirred overnight atrt The reaction mixture was diluted with ethyl acetate (20 mL) andwashed with dilute hydrochloric acid (2×20 mL, 0.1 M), water (2×20 mL),brine (2×20 ml), dried over sodium sulfate, filtered and evaporated toobtain the title compound (80 mg, crude, 50%, used directly in the nextstep). ESMS: 474 (M)⁺, 475 (M+1)⁺, 533 (M+59)⁻.

Preparation 190(1S,3R)(3-{[(Biphenyl-4-carbonyl)amino]methyl}-cyclopentyl)carbamic acidt-butyl ester

[0619] A solution of a compound from preparation 183 (68 mg, 0.31 mmol),4-phenyl benzoyl chloride (82 mg, 0.38 mmol), triethyl amine (0.5 mL),and DMAP (10 mg) dissolved in DMF (2 mL) was stirred for four hours atrt. The reaction mixture was diluted with ethyl acetate (20 mL) andwashed with dilute hydrochloric acid (2×20 mL, 0.1 M), water (2×20 mL),brine (2×20 mL), dried over sodium sulfate, filtered and evaporated toobtain the title compound (170 mg, crude, used without purification).ESMS:395 (M+1)⁺, 453 (M+59)⁻.

Preparation 191 (1S,3R)-Biphenyl-4-carboxylic acid(3-amino-cyclopentylmethyl)amide

[0620] A compound from preparation 190 (170 mg, crude) was dissolved intrifluoro acetic acid (2 mL) and stirred for half an hour. The reactionmixture was evaporated under vacuum and the residue was dissolved inmethylene chloride and filtered through scx column (Bond Elut, 60 cc)and eluted with methanol-ammonia solution (2M) to obtain the titlecompound (63 mg). ESMS: 295 (M+1)⁺, 353 (M+59)⁻

Preparation 192(1S,3R)-3-(2-Chloro-6-fluorophenyl)₅-methylisoxazole-4-carboxylic acid(3-{[(biphenyl-4-carbonyl)amino]methyl}-cyclopentyl)amide

[0621] A solution a compound from preparation 191 (63 mg, 1.21 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (88 mg, 0.32 mmol), triethylamine (0.5 mL), and DMAP (10 mg) dissolved in DMF (5 mL) was stirred forfour hours at rt. The reaction mixture was diluted with ethyl acetate(20 mL) and washed with dilute hydrochloric acid (2×20 mL, 0.1 M), water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered andevaporated to obtain the title compound (61 mg, 54%, used withoutpurification). ESMS: 532 (M)⁺, 533 (M+1)⁺, 591 (M+59)⁻.

Preparation 193(1S,3R)(3-{[(Pyridine-3-carbonyl)amino]methyl}cyclopentyl)carbamic acidt-butyl ester

[0622] A solution of a compound from preparation 183 (68 mg, 0.31 mmol),nicotinoyl chloride (54 mg, 0.38 mmol), triethyl amine (0.5 mL), andDMAP (10 mg) dissolved in DMF (2 mL) was stirred for four hours at rt.The reaction mixture was diluted with ethyl acetate (20 mL) and washedwith water (2×20 mL), brine (2×20 mL), dried over sodium sulfate,filtered and evaporated to obtain the title compound (58 mg, 59%, usedwithout purification). ESMS: 318 (M−1)-, 378 (M+59)⁺.

Preparation 194 (1S,3R)-N-(3-Aminocyclopentylmethyl)nicotinamide

[0623] A compound from preparation 193 (58 mg, crude) was dissolved intrifluoroacetic acid (2 mL) and stirred for half an hour. The reactionmixture was evaporated under vacuum and the residue was dissolved inmethylene chloride and filtered through scx column (Bond Elut, 60 cc)and eluted with methanol-ammonia solution (2M) to obtain the titlecompound (quantitative). ESMS: 220 (M+1)⁺, 278 (M+59)⁻.

Preparation 195(1S,3R)-N-(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}cyclopentylmethyl)-nicotinamide

[0624] A solution of a compound from preparation 194 (112 mg, 0.51mmol), 2-chloro-6-fluoro phenyl isoxazoyl chloride (210 mg, 0.76 mmol),triethyl amine (0.5 mL), and DMAP (10 mg) dissolved in DMF (5 mL) wasstirred for four hours at rt. The reaction mixture was diluted withethyl acetate (20 mL) and washed water (2×20 mL), brine (2×20 mL), driedover sodium sulfate, filtered and evaporated to obtain the titlecompound (104 mg, 28%, used without purification). ESMS: 455 (M−1)⁻, 515(M+59)⁻.

Preparation 196(1S,3R)(3-{[(Furan-2-carbonyl)amino]methyl}cyclopentyl)-carbamic acidt-butyl ester

[0625] A solution of a compound from preparation 183 (68 mg, 0.31 mmol),2-furoyl chloride (50 mg, 0.38 mmol), triethyl amine (0.5 mL), and DMAP(5 mg) dissolved in DMF (2 ml) was stirred for four hours at rt. Thereaction mixture was diluted with ethyl acetate (20 mL) and washed withwater (2×20 mL), brine (2×20 mL), dried over sodium sulfate, filteredand evaporated to obtain the title compound (105 mg, crude, used withoutpurification) ESMS: 309 (M+1)⁺, 343 (M+35)⁻.

Preparation 197 (1S,3R)-Furan-2-carboxylic acid(3-aminocyclopentylmethyl)-amide

[0626] A compound from preparation 196 (105 mg, crude) was dissolved intrifluoroacetic acid (2 mL) and stirred for half an hour. The reactionmixture was evaporated under vacuum and the residue was dissolved inmethylene chloride and filtered through SCX (Bond Elut, 60 cc) columnand eluted with methanol-ammonia solution to obtain the title compound(94 mg, quantitative). ESMS: 209 (M+1)⁺.

Preparation 198(1S,3R)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid(3-{[(furan-2-carbonyl)amino]methyl}-cyclopentyl)amide

[0627] A solution of a compound from preparation 197 (94 mg, 0.51 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (185 mg, 0.67 mmol),triethyl amine (0.5 mL), and DMAP (10 mg) dissolved in DMF (5 mL) wasstirred for four hours at rt. The reaction mixture was diluted withethyl acetate (20 mL) and washed water (2×20 mL), brine (2×20 mL), driedover sodium sulfate, filtered and evaporated to obtain the titlecompound (147 mg, crude, quantitative, used without purification). ESMS:446 (M+1)⁺, 504 (M+59)⁻.

Preparation 199(1S,3R){3-[(3,4,5-Trimethoxybenzoylamino)methyl]cyclopentyl}carbamicacid t-butyl ester

[0628] A solution of a compound from preparation 183 (68 mg, 0.31 mmol),3,4,5-trimethoxy benzoyl chloride (88 mg, 0.38 mmol), triethyl amine(0.5 mL), and DMAP (10 mg) dissolved in DMF (2 mL) was stirred for fourhours at rt. The reaction mixture was diluted with ethyl acetate (20 mL)and washed with water (2×20 mL), brine (2×20 mL), dried over sodiumsulfate, filtered and evaporated to obtain the title compound (130 mg,crude, used without purification). ESMS:409 (M+1)⁺, 443 (M+35).

Preparation 200(1S,3R)-N-(3-Aminocyclopentylmethyl)-3,4,5-trimethoxybenzamide

[0629] A compound from preparation 199 (130 mg, crude) was dissolved intrifluoroacetic acid (2 mL) and stirred for half an hour at rt. Thereaction mixture was evaporated under vacuum and the residue wasdissolved in methylene chloride and filtered through SCX (Bond Elut, 60cc) column and eluted with methanol-ammonia solution (2M) to obtain thetitle compound (82 mg, 83%). ESMS: 309 (M+1)⁺, 367 (M+59)⁻.

Preparation 201(1S,3R)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid{3-[(3,4,5-trimethoxybenzoylamino)methyl]cyclopentyl}amide

[0630] A solution of a compound from preparation 200 (82 mg, 0.26 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (109 mg, 0.39 mmol),triethylamine (0.5 mL), and DMAP (10 mg) dissolved in DMF (5 mL) wasstirred for four hours at rt The reaction mixture was diluted with ethylacetate (20 mL) and washed water (2×20 mL), brine (2×200 mL), dried oversodium sulfate, filtered and evaporated to obtain the title compound (89mg, 62%, used without further purification). ESMS: 546 (M+1)⁺, 604(M+59)⁻.

Preparation 202(1S,3R)[3-(Benzyloxycarbonylaminomethyl)cyclopentyl]carbamic acidt-butyl ester

[0631] A solution of a compound from preparation 183 (1.3 g, 6 mmol),CBZ chloride (1.2 g, 7 mmol), triethyl amine (1 mL), and DMAP (50 mg)dissolved in DCM (50 mL) was stirred for four hours at rt. The reactionmixture was diluted with ethyl acetate (20 mL) and washed with water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered andevaporated to obtain the title compound (2.0 g, crude). ESMS: 349(M+1)⁺, 407 (M+59)⁻.

Preparation 203 (1S,3R)(3-Aminocyclopentylmethyl)carbamic acid benzylester

[0632] A compound from preparation 202 (2.00 g, crude) was dissolved intrifluoroacetic acid (10 mL) and DCM (10 mL) and stirred for half anhour at rt. The reaction mixture was evaporated under vacuum and theresidue was dissolved in DCM and filtered through SCX (Bondesil, 20 g)column and eluted with methanol-ammonia solution (2M) to obtain thetitle compound (550 mg, 38%). ESMS: 249 (M+1)⁺.

Preparation 204(1S,3R)(3-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}cyclopentylmethyl)carbamicacid benzyl ester

[0633] A solution of a compound from preparation 203 (500 mg, 2 mmol),2-chloro-6-fluorophenyl isoxazoyl chloride (600 mg, 2.2 mmol),triethylamine (1 mL), and DMAP (100 mg) dissolved in DMF (10 mL) wasstirred for four hours at rt. The reaction mixture was diluted withethyl acetate (20 mL) and washed water (2×20 mL), brine (2×20 mL), driedover sodium sulfate, filtered, evaporated and chromatographed (Sicolumn, 12×2.5 inches, gradient −10% to 50% ethyl acetate in hexanes) toobtain the title compound (355 mg, 36%). ESMS: 486 (M+1)⁺, 544 (M+59)⁻.

Preparation 205(1S,3R)(3-{[2-(3,4,5-Trimethoxyphenyl)acetylamino]methyl}-cyclopentyl)carbamicacid t-butyl ester

[0634] A solution of a compound from preparation 183 (1 g, 4.6 mmol),3,4,5-trimethoxy phenylaceticacid (1.5 g, 6.9 mmol), EDC (1.3 g, 6.9mmol) and DMAP (100 mg) dissolved in DCM (20 mL) was stirred overnightat rt. The reaction mixture was washed with water (2×20 mL), brine (2×20mL), dried over sodium sulfate, filtered, and evaporated to obtain thetitle compound (1.5 g, crude). ESMS: 423 (M+1)⁺, 481 (M+59)⁻.

Preparation 206(1S,3R)-N-(3-Aminocyclopentylmethyl)-2-(3,4,5-trimethoxy-phenyl)acetamide

[0635] A compound from preparation 205 (1.5 g) was dissolved and stirredin a solution of hydrogen chloride in acetic acid(20 mL, 1M) for half anhour at rt. The reaction mixture was evaporated and the residue wastriturated with ether to obtain the title compound (1.1 g, used withoutfurther purification). ESMS:323(M+1)⁺, 357 (M+35)⁻.

Preparation 207(1S,3R)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid(3-{[2-(3,4,5-trimethoxyphenyl)acetyl-amino]methyl}cyclopentyl)amide

[0636] A solution of a compound from preparation 206 (1 g, 3.1 mmol),2-chloro-6-fluoro phenyl isoxazoyl chloride (850 mg, 3.1 mmol),triethylamine (1 mL), and DMAP (100 mg) dissolved in DCM (20 mL) wasstirred for four hours at rt. The reaction mixture was washed with water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered,evaporated and chromatographed (Si column, 15×6 cm, 50% ethyl acetate inhexane) to obtain the title compound (1.2 g, 70%). ESMS: 486 (M+1)⁺, 544(M+59)⁻.

Preparation 208(1S,3R)[3-({[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}methyl)cyclopentyl]carbamicacid t-butyl ester

[0637] A mixture of a compound from preparation 183 (215 mg, 1 mmol),2-chloro, 6-fluoro phenyl isoxazoyl chloride (300 mg, 1.1 mmol),triethyl amine (0.1 mL) and DMAP (20 mg) dissolved in DMF (5 mL) wasstirred overnight at r.t. The reaction mixture was diluted with ethylacetate (25 mL) and washed with HCl (1M, 2×10 mL), water (2×10 mL),brine (2×10 mL), dried over sodium sulfate, filtered, and evaporated toyield the title compound (400 mg, 88%, crude). ESMS: 452 (M+1)⁺.

Preparation 209[3-({[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}methyl)cyclopentyl]carbamicacid t-butyl ester

[0638] A mixture of a compound from preparation 176 (640 mg, 2.9 mmol),2-chloro, 6-fluoro phenyl isoxazoyl chloride (1.22 g, 4.4 mmol),triethyl amine (0.5 mL) and DMAP (50 mg) dissolved in DCM (50 mL) wasstirred overnight at rt. The reaction mixture was washed with HCl (1M,2×10 mL), water (2×10 mL), brine (2×10 mL), dried over sodium sulfate,filtered, and evaporated to yield the title compound (1.5 g, crude,quantitative). ESMS: 452 (M+1)⁺.

Preparation 210 N-(3-aminocyclohexyl)(t-butoxy)carboxamide

[0639] To 1,3 diaminocyclohexyl (20.0 g, 175 mmol) in 400 mL CHCl₃ at 0°C. was added di-t-butyldicarbonate (7.65 g, 35.0 mmol), which wasdissolved in 100 mL CHCl₃, poured rapidly. The ice bath was removed andafter 0.5 h, the reaction mixture was washed with saturated NaHCO₃(3×150 mL) and washed with brine (2×150 mL). The organics wereconcentrated to give (cis and trans, 2:1) a crude clear oil (7.50 g,100%). The crude product was used without purification.

Preparation 211 and 212N-((1S,3S)-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyamino}cyclohexyl)(t-butoxy)carboxamide &N-((3S,1R)-3-{[3-(2-chloro-4-fluorophenyl)-5-methylisoxazol-4-yl]carbonyamino}cyclohexyl)(t-butoxy)carboxamide

[0640] To the crude oil from preparation 210 (7.50 g, 35.0 mmol) in 75mL anhydrous CH₂Cl₂ at 0° C. was added Et₃N (7.32 mL, 52.5 mmol)followed by 3-(6-chloro-2-fluorophenyl)-5-methylisoxazole-4-carbonylchloride (10.01 g, 38.5 mmol). After 5 min. the ice bath was removed andthe reaction stirred for an additional 25 minutes. The reaction wasdiluted with 300 mL CH₂Cl₂ and washed with saturated NaHCO₃ (100 mL).The organics were dried over Na₂SO₄, filtered and concentrated until aprecipitate formed. The precipitate was filtered and the filtrate wasconcentrated a little more to give more precipitate, which was filtered.A total of 8.5 g (54%) of preparation 209 was obtained. The filtrate wasconcentrated and chromatographed with 20-30% EtOAc in hexanes to give3.78 g (24%) of preparation 210.

[0641] ESIMS m/e 451 ³⁵Cl (M⁺+1) and 453 ³⁷C (M⁺+1).

[0642] ESIMS m/e 452 ³⁵Cl (M⁺+1) and 454 ³⁷Cl (M⁺+1).

Preparation 213Cis-3-(amino)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanehydrochloride

[0643] To Example 495 (0.500 g, 1.16 mmol) at 0° C. was added 4M HCl indioxane (5 mL) to give a suspension. The reaction was sonicated at r.t.for 2 min., then stirred at r.t. for 45 minutes. A yellow solid wasobtained (0.411 g, 96%). ESIMS m/e 332 ³⁵CI (M⁺+1) and 334 ³⁷C1 (M⁺+1).

Preparation 214 d,l-trans-Octahydroquinolin-2-one

[0644] Following the literature procedure of Morzycki et al(Heterocycles, (1995), 41 (12), 2729-2736)3,4,5,6,7,8-hexahydro-1H-quinolin-2-one (100 mg, 0.66 mmol) in dioxane(10 ml) with trifluoroacetic acid (0.042 ml, catalytic) was treated withNaCNBH₃ (0.67 g, 10.8 mmol), and stirred for 18 hr at RT. The mixturewas then diluted with EtOAc and washed with dilute HCl (0.1 N).Additional EtOAc extractions (2×) were then combined with the first, andthen treated with sat'd bicarbonate, brine, dried over Na₂SO₄, filteredand concentrated to afford the mainly trans product (98 mg, ˜5:1). MS(+ES) 154 (M+H)+.

Preparation 215 3-(2-Amino-trans-cyclohexyl)propionic acid methyl esterhydrochloride

[0645] A compound from preparation 214 (1 g, 6.4 mmol) was dissolved inmethanol (100 mL) and conc. HCl (10 mL) and refluxed for 20 h. Thesolvents were removed under vacuum to obtain the title compound (1.05 g,88%). ESMS: 186 (M)⁺, 187 (M+1)⁺.

Preparation 2163-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}trans-cyclohexyl)propionicacid methyl ester

[0646] To a solution of a compound from preparation 215 (1 g, 4.5 mmol)dissolved in DMF (50 mL), was added 2-chloro-6-fluorophenyl isoxazoylchloride (1.23 g, 4.5 mmol), triethyl amine (10 mL) and DMAP (100 mg)and stirred overnight at rt. The reaction mixture was diluted with ethylacetate (100 mL) and washed with 1M HCl (2×50 mL), water (2×50 mL),brine (2×50 mL), dried over sodium sulfate, filtered and evaporated toyield 1.9 g. ESMS: 423 (M+1)⁺, 481 (M+Ac)⁻.

Preparations 217 and 218 Separation of Preparation 216 into Enantiomers

[0647] Preparative separation into enantiomers was achieved by columnchromatography over a Chiralpak AD column using 40% isopropyl alcohol inheptane and 0.2% dimethylethylamine. Thus, the first enantiomer thateluted was designated preparation 217 (Isomer 1), and the second,preparation 218 (Isomer 2).

Preparation 2193-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}trans-cyclohexyl)propionicacid

[0648] A solution from preparation 217 (0.127 g, 0.3 mmol) in THF (5 mL)was treated with a 0.5 M soln of LiOH in water (3 mL). The sol'n wasstirred at r.t. for 5 hr. The reaction was diluted with water (3 mL) andwashed with EtOAc (2×5 mL). The pH of the aqueous was adjusted to −3with 0.1 M HCl and extracted with EtOAc (4×5 mL). The organicextractions were then washed with brine (2×5 mL), dried over sodiumsulfate and the solvent removed to afford 0.095 g (80%) as a whitesolid. MS (ES+) m/z 409.0 (M+H)⁺, (ES—) m/z 407.0 (M−H).

Preparation 2203-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]trans-cyclohexyl}amide

[0649] A sol'n from preparation 219 (0.095 g, 0.23 mmol) and EDC (0.115g, 0.6 mmol) in DMF (25 mL) was treated with 3,4,5 trimethoxyaniline(0.11 g, 0.6 mmol). A catalytic amount of DMAP (4 mg, 0.03 mmol) wasalso added. The reaction mixture was stirred at r.t. overnight. Thereaction was diluted in EtOAc (100 mL) and washed with 5% citric acidsol'n (3×50 mL), water (2×50 mL), and dried over sodium sulfate. Thesolvent was removed in vacuo to afford a crude brown oil which waspurified by a Varian Bond Elut SI column (10 g) with an eluting solventof 1:1 hexanes:EtOAc. The solvent was removed in vacuo to afford 0.072 g(54%) as an off white solid. MS (ES+) m/z 574.0 (M+H)⁺, (ES−) m/z 572.1(M−H)⁻, 632.1 (M+CH₃COO⁻)⁻.

Preparation 221 d,l-cis-Octahydroquinolin-2-one

[0650] 2-Nitrocinnamic acid (17 g, 82 mmol) was dissolved in acetic acid(120 ml) and treated with PtO₂ (10 g) and H₂ (3 atm) for 24 hr at 60° C.The crude reaction was then cooled to r.t., filtered and concentrated.The material was then diluted with EtOAc, and sat'd bicarbonate. Afterreextraction of the aqueous phase with EtOAc (2×), the combined organicswere washed with brine, dried over Na₂SO₄, filtered and concentrated toafford a 13:1 mixture of cis/trans product (10 g, 80%). Clean cis isomereventually crystallized from residual solvent. MS (+ES) 154 (M+H)+.

Preparation 222 3-(2-Amino-cis-cyclohexyl)propionic acid methyl esterhydrochloride

[0651] A solution of a compound from preparation 221 (4.4 mg, 28.9 mmol)in methanol (50 mL) was treated with conc. HCl (10 mL) and refluxedovernight. The reaction mixture was evaporated to yield the titlecompound (7 g, crude, quantitative). ESMS+: 186 (M+1).

Preparation 2233-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl]amino}-cis-cyclohexyl)propionicacid methyl ester

[0652] A compound from preparation 222 (7 g, 0.038 mmol) was dissolvedin CH₂Cl₂ (100 mL) and treated with methyl isoxazoyl chloride (11 g,0.04 mmol) in presence of triethylamine (20 mL) at room temperature for4 h. The reaction mixture was washed with 1 N HCl (2×100 mL), water(2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered andevaporated to give the title compound (crude gun, 10 g, 62%). ESMS+: 430(M), 424 (M+1).

Preparation 2243-(2-{[3-(2-Chloro-6-fluorophenyl)-5-methylisoxazolecarbonyl]amino}-cis-cyclohexyl)propionicacid

[0653] A solution of a compound from preparation 223 (8.5 g, 20 mmol)dissolved in THF (200 mL) and LiOH (100 mL, 0.5 M solution) was stirredfor 2 h at r.t. The reaction was diluted with water (50 mL) and washedwith EtOAc (2×100 mL). The alkaline aqueous solution was acidified to pH1 with conc. HCl and extracted with EtOAc (3×200 mL). The organicextract was washed with brine, dried over sodium sulfate, filtered andevaporated to yield a white solid (8 g, 97%). ESMS+: 409 (M+1).

Preparation 2253-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]-cis-cyclohexyl}amide

[0654] A solution of a compound from preparation 224 (1 g, 2.4 mmol),EDC (955 mg, 5 mmol), trimethoxyaniline (915 mg, 5 mmol), and DMAP (50mg, catalytic) in DMF (50 mL) was stirred at r.t. overnight. Thereaction mixture was diluted with EtOAc (200 mL) and washed with dil.HCL (1 M, 3×100 mL), water (3×100 mL), brine (2×100 mL), dried oversodium sulfate, filtered and evaporated to give the title compound (1.3g, 97%). ESMS+: 574 (M), 576 (M+2).

Preparation 227 3-(2-{[5-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4carbonyl]amino}cyclohexyl)propionic acid methyl ester

[0655] 5-(6-Chloro-2-fluorophenyl)-3-methylisoxazole-4-carboxylic acid(0.4 mmol) was prepared as described previously, and added to a MeCl₂solution (10 ml) of a compound from preparation 222 (222 mg, 1.2 eq)followed by Et₃N (133 ml, 0.96 mmol) and DMAP (10%) at r.t. Acylationwas allowed to proceed for 18 h. Crude product was obtained by dilutionof the reaction mixture with MeCl₂ and 0.1 N HCl, transferring to aseparatory funnel. The organic phase was then washed with sat'dbicarbonate, brine, then dried over Na₂SO₄. Filtration and concentrationprovided crude product, which was then purified using a Bond-Elut Sicolumn (1 g, 1:1 hex/EtOAc) to generate the title compound (86 mg, 51%).MS (+ES) m/z 422.9/424.9 (M+H).

Preparation 2273-(2-{[5-(2-Chloro-6-fluoro-phenyl)-3-methyl-isoxazole-4-carbonyl]-amino}-cyclohexyl)-propionicacid

[0656] To a solution of the compound from 226 (86 mg, 0.2 mmol) in THF(5 ml) was added 2 ml 0.5M aq. LiOH (5 eq), dropwise at r.t. Hydrolysiswas complete at 2.5 hr. After dilution with water and EtOAc, thecontents were transferred to a separatory funnel, where addition ofenough 1N HCl was added to maintain pH 2. The aqueous phase was backextracted 3 times with additional solvent, and the combined organicswere then washed with brine, dried over Na₂SO₄. Filtration andconcentration afforded clean acid, 80 mg (97%), which was used withoutfurther purification. MS (+ES) m/z 408.9/410.9 (M+H).

Preparation 2285-(2-Chloro-6-fluorophenyl)-3-methylisoxazole-4-carboxylicacid-{2-[2-(3,4,5-trimethoxyphenylcarbamoyl)ethyl]cyclohexyl}amide

[0657] To the acid from preparation 227 (40 mg, 0.1 mmol) in DMF (2 ml)was added catalytic amount of DMAP (10%, 1 mg), followed by EDC.HCl(20.6 mg, 0.11 mmol) and 3,4,5-trimethoxyaniline (20.1 mg, 0.11 mmol) atr.t. After 18 hr, the reaction was transferred to a separatory funneland diluted with EtOAc and 1N NaOH (aq. pH 9-10). The aqueous phase wasextracted 3 times, and combined EtOAc fractions were then washedsequentially with 1 N HCl, sat'd bicarbonate, brine, and then dried overNa₂SO₄. After filtration and concentration, crude amide was obtained (33mg). Starting material (7 mg) was also recovered from the aqueousfraction upon acidification and standard work-up. The crude product wasthen chromatographically purified (Bond-Elut Silica column, 1 g, 2:1EtOAc/hexanes) to afford clean amide (48 mg, 50%). MS (ES+) 573.9, 575.9(M+H)+.

Preparation 229 Methyl 3-(2-aminocyclohexyl)propanoate hydrochloride

[0658] A solution of a compound from preparation 163 (4.4 mg, 28.9 mmol)in methanol (50 mL) was treated with conc. HCl (10 mL) and refluxedovernight. The reaction mixture was evaporated to yield the titlecompound (7 g, crude, quantitative). ESMS⁺: 186 (M+1).

Preparation 230 Methyl3-(2-{[3-(6-chloro-2-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cyclohexyl)propanoate

[0659] A compound from preparation 229 (7 g, 0.038 mmol) was dissolvedin methylene chloride (100 mL) and treated with methyl isoxazoylchloride (11 g, 0.04 mmol) in presence of triethylamine (20 mL) at roomtemperature for four hours. The reaction mixture was washed with 1 N HCl(2×100 mL), water (2×100 mL), brine (2×100 mL), dried over sodiumsulfate, filtered and evaporated to give the title compound (crude gum,10 g, 62%). ESMS+: 430 (M), 424 (M+1).

Preparation 2313-(2-{[3-(6-chloro-2-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino)cyclohexyl)propanoicacid

[0660] A solution of the ester from preparation 230 (8.5 g, 20 mmol)dissolved in THF (200 mL) and LiOH (100 mL, 0.5 M solution) was stirredfor 2 h at rt. LiOH solution was diluted with water (50 mL) and washedwith ethyl acetate (2×100 mL). The alkaline aqueous solution wasacidified to pH 1 with conc. HCl and extracted with ethyl acetate (3×200mL). The ethyl acetate extract was washed with brine, dried over sodiumsulfate, filtered and evaporated to yield a white solid (8 g, 97%).ESMS+: 409 (M+1).

Preparation 2323-(2-([3-(6-chloro-2-fluorophenyl)-5-methylisoxazolyl]carbonylamino}cyclohexyl)-N-(3,4,5-trimethoxyphenyl)propanamide

[0661] A solution of acid from preparation 231 (1 g, 2.4 mmol), EDC (955mg, 5 mmol), trimethoxyaniline (915 mg, 5 mmol), and DMAP (50 mg,catalytic) in DMF (50 mL) was stirred at r.t. overnight. The reactionmixture was diluted with ethyl acetate (200 mL) and washed with dil. HCL(1 M, 3×100 mL), water (3×100 mL), brine (2×100 mL), dried over sodiumsulfate, filtered and evaporated to give the title compound (1.3 g,97%). ESMS+: 574 (M), 576 (M+2).

Preparation 233 6-Fluoropyridine-2-carboxylic acid

[0662] To a heterogeneous solution of 2-fluoro-6-methyl-pyridine (9.65g, 86.8 mmol) in water (400 mL) was added potassium permanganate (31.6g, 200 mmol), and the reaction was heated to approximately 100° C. After30 minutes, additional potassium permanganate (16.5 g, 104 mmol) wasadded, and the reaction heated at 100° C. overnight. The reaction wasfiltered through celite to remove manganese salts. The mother liquor waswashed with ethyl ether (200 mL×3), neutralized to pH 7, andconcentrated down to approximately 100 mL total volume. The aqueoussolution was acidified to pH 2 with concentrated HCl and extracted withethyl acetate, followed by 20% i-PrOH(CHCl₃ (×3). The combined organiclayers were dried over MgSO₄ and concentrated. The solids were suspendedin chloroform, sonicated, then filtered to remove remaining sideproducts. The mother liquor was concentrated to give 5.47 g as a whitecrystalline solid, 45% yield. ¹H NMR: consistent with structure. MS (ionspray) 140).

Preparation 234 6-Methoxy-pyridine-2-carboxylic acid

[0663] To 6-hydroxypicolinic acid (1.39 g, 10.0 mmol) in toluene (35 mL)was added silver oxide (2.43 g, 10.5 mmol) and the mixture was stirredfor 30 minutes. To the reaction was added iodomethane (1.31 mL, 21.0mmol), and the reaction was heated to reflux overnight. The reaction wasfiltered over celite and concentrated to give 1.45 g of the methyl esteras a yellow solid. The resulting solid was dissolved in tetrahydrofuran(50 mL), and added to a solution of 5N NaOH (20 mL, 100 mmol) and water(5 mL). After one hour, the reaction was acidified to pH 3 with 5N HCland concentrated. To the resulting white solids was added 20% MeOH/CHCl₃and the mixture was sonicated for 20 minutes. The mixture was filtered,and the mother liquor was dried over MgSO₄ and concentrated to give 1.33g of the title compound as a white solid, 87% yield. ¹H NMR: consistentwith structure. MS (ion spray) 152 (M⁻).

Preparation 235 5-Methoxy-nicotinic acid

[0664] To sodium hydride (0.42 g, 10.5 mmol, washed with hexanes ×3) indimethylformamide (15 mL) was added 5-hydroxy-nicotinic acid methylester (1.53 g, 10.0 mmol) in dimethylformamide (10 mL). After threeminutes, iodomethane (0.65 mL, 10.5 mmol) was added dropwise whilestirring at room temperature. After 1 h, the reaction was quenched withmethanol and concentrated to a brown oil. The solution was dissolved in20% isopropanol/chloroform, washed with saturated aqueous sodiumbicarbonate solution, brine (×3), dried over magnesium sulfate andconcentrated to give 1.46 g of 6-methoxynicotinic acid methyl ester. Theresulting oil was dissolved in tetrahydrofuran (50 mL), and added to asolution of 5N NaOH (20 mL, 100 mmol) and water (5 mL). After 30minutes, an additional 25 mL of 5N NaOH was added to the solution. Afterone hour, the reaction was acidified to pH 3 with 5N HCl andconcentrated. To the resulting white solids was added 20% MeOH/CHCl₃ andthe mixture was sonicated for 20 minutes. The mixture was filtered, andthe mother liquor was dried over MgSO₄ and concentrated to give 1.38 gas a light yellow solid, 90% yield. ¹H NMR: consistent with structure.MS (ion spray) 152 (M).

Preparation 236 N-{3-[3-(1-Aminoethylidene)-5-chloro2,4-dioxo-3,4-dihydro-2H-quinolin-1-y]-cyclohexylmethyl}benzamide

[0665] A compound from Example 125 (0.05 g, 0.1 mmol) and Mo(CO)₆ (0.3g, 1.1 mmol) were combined in a solution of ACN (5 mL) and water (1 mL).The reaction mixture was heated to 60° C. while stirring. After 3 hr ofstirring the reaction was complete. The reaction was concentrated to adark brown solid under vacuum. The solid was diluted in CH₂Cl₂ (1 mL)and purified by passing through a Varian Bond Elut SI column (5 g). Theproduct was eluted with 2% MeOH in CH₂Cl₂. The solvent was removed invacuo to afford 0.041 g (82%) of the title compound as a light brownsolid. MS (ES+) m/z 452.0 (M+H)⁺, (ES−) 450.0 (M−H)⁻.

Preparation 237{3-[3-(1-Aminoethylidene)-5-chloro-2,4-dioxo-3,4dihydro-2H-quinolin-1-yl]-cyclohexylmethyl}carbamicacid benzyl ester

[0666] A compound from Example 498 (0.25 g, 0.5 mmol) and Mo(CO)₆ (1.35g, 5.2 mmol) were combined in a solution of ACN (25 mL) and water (5mL). The reation mixture was heated to 60° C. while stirring. Afterstirring overnight the reaction was complete. The reaction wasconcentrated to a dark brown solid under vacuum. The solid was dilutedin CH₂Cl₂ (10 mL) and the solid material was filtered by passing throughCelite. The yellow filtrate was purified by silica gel columnchromatography using 50% EtOAc in CH₂Cl₂ to elute the product. Thesolvent was removed in vacuo to afford 0.24 g (98%) of the titlecompound as a light yellow solid. MS (ES+) m/z 481.9 (M+H)⁺, (ES−) 479.9(M−H)⁻.

Preparation 238N-{3-[3-(1-Aminoethylidene)₅-chloro-2,4-dioxo-3,4-hydro-2H-quinolin-1-yl]-cyclohexylmethyl}nicotinamide

[0667] A compound from Example 126 (0.02 g, 0.04 mmol) and Mo(CO)₆ (0.13g, 0.5 mmol) were combined in a solution of ACN (5 mL) and water (1 mL).The reaction mixture was heated to 60° C. and stirred for 2 hr. Thereaction was concentrated to a dark brown solid under vacuum. The solidwas diluted in CH₂Cl₂ (10 mL) and purified by passing directly through aBond-Elut cation exchange column. The product was eluted with 2M Ammoniain MeOH. The brown liquid was filtered using a Gelman Nylon Acrodisc toafford a yellow solution. The solvent was removed in vacuo to afford0.018 g (90%) of the title compound as a white solid. MS (ES+) m/z 452.9(M+H)⁺, (ES−) m/z 450.8 (M−H)⁻, 510.9 (M+CH3COO⁻)⁻.

Preparation 239N-{3-[3-(1-Aminoethylidene)-5-chloro-2,4-dioxo-3,4-dihydro-2H-quinolin-1-yl]-cyclohexylmethyl}-6-fluoronicotinamide

[0668] A compound from Example 149 (0.05 g, 0.1 mmol) and Mo(CO)₆ (0.3g, 1.1 mmol) were combined in a solution of ACN (5 mL) and water (1 mL).The reaction mixture was heated to 60° C. while stirring. After 3 hr ofstirring the reaction was complete. The reaction was concentrated to adark brown solid under vacuum. The solid was diluted in CH₂Cl₂ (1 mL)and purified by passing through a Varian Bond Elut SI column (5 g). Theproduct was eluted with 2% MeOH in CH₂Cl₂. The solvent was removed invacuo to afford 0.041 g (82%) of the title compound as a light brownsolid. MS (ES+) m/z 452.0 (M+H)⁺, (ES−) 450.0 (M−H)⁻.

Preparation 240N-{3-[5-Chloro-3-(1-hydroxy-ethylidene)-2,4-dioxo-3,4-dihydro-2H-quinolin-1-yl]-cyclohexylmethyl}benzamide

[0669] A compound from preparation 236 (0.05 g, 0.11 mmol) was stirredin a solution of acetonitrile (10 mL) and water (1 mL). The solution wastreated with p-toluenesulfonic acid (0.01 g, 0.05 mmol). The reactionwas heated to reflux and stirred overnight. The reaction wasconcentrated to a solid and diluted in EtOAc (50 mL). The organic waswashed with sat'd sodium bicarbonate (2×10 mL), brine (2×10 mL), anddried over sodium sulfate. The solvent was removed to yield a crudesolid that was purified using a chromatotron with a silica gel plate.The product was eluted with 50% EtOAc in CH₂Cl₂. The solvent was removedto afford 0.032 g (64%) of the tide compound as an off-white solid. MS(ES+) m/z 452.9 (M+H)⁺, (ES−) 450.9 (M−H)⁻.

Preparation 241 (3-Aminocyclohexylmethyl)carbamic acid benzyl ester

[0670] S-Amino enantiomer of a compound from preparation 104 (0.28 g,0.77 mmol) was treated with HCl in HOAc (1.0M, 2 mL) under N₂. After 20min of stirring at r.t., the reaction was complete. The crude was thenconcentrated to a solid using CAN to azeotrope the solvent. The whitesolid was taken up in ether and filtered. The white solid weighed 0.19 g(95%) and was in good purity. MS (ES+) m/z 263.0 (M+H)⁺.

Preparation 242 t-Butylaminophenylacetic acid methyl ester

[0671] t-Butylamine (9.350 mL, 88.0 mmol) was combined withα-bromophenylacetic acid (5.0 g, 22.0 mmol) and triethylamine (3.40 mL,22.0 mmol) in tetrahydrofuran (200 mL) and the mixture refluxedovernight. The mixture was then concentrated in vacuo and the residuetaken up in 20% isopropanol/chloroform and washed 1× aqueous NaHCO₃, ×2brine, and dried over sodium sulfate. Concentration left a residue whichwas loaded onto a silica gel column and eluted with methanol/chloroformto yield pure amine (1.34 g, 28%) as an oil. MS(ES): (M+1)⁺ 222.2, 223.2m/z.

Preparation 243 t-Butylaminophenylacetic acid

[0672] A compound from preparation 242 (1.32 g, 6.0 mmol) was combinedwith aqueous 2N sodium hydroxide (20 mL), tetrahydrofuran (5 mL), andethanol (5 mL) and the mixture stirred overnight at ambient temperature.The mixture was then adjusted to approx. pH 2.5 with aqueoushydrochloric acid and concentrated to dryness in vacuo. The resultingsolids were then slurried and washed with 20% ethanol/ethyl acetate.Concentration of the filtrate left crude amino acid derivative (0.94 g,75%) as an off white solid which was used without further purification.MS(ES): (M+1)⁺ 208.2 m/z.

Preparation 244 (2,2-Dimethylpropylamino)phenylacetic acid methyl ester

[0673] Neopentylamine (5.13 mL, 43.6 mmol) was combined withα-bromophenylacetic acid (5.00 g, 22.0 mmol) and triethylamine (3.65 mL,26.2 mmol) in tetrahydrofuran (60 mL) and the mixture overnight atambient temperature. The mixture was then diluted with ethyl acetate,washed with water, and dried over sodium sulfate. Concentration left aresidue, which was loaded onto a silica gel column and eluted withmethanol/chloroform to yield 3.38 g (66%) of pure amine as an oil.MS(FS): (M+1)⁺ 236.1, 237.1 m/z.

Preparation 245 (2,2-Dimethylpropylamino)phenylacetic acid

[0674] An amine from preparation 244 (3.20 g, 13.6 mmol) was combinedwith aqueous 2N sodium hydroxide (30 mL), tetrahydrofuran (10 mL), andethanol (5 mL) and the mixture stirred overnight at ambient temperature.The mixture was then treated in a manner similar to that in preparation11 which left crude amino acid derivative (0.337 g, 11%) as a whitesolid and was used without further purification. MS(ES): (M+1)+222.1m/z.

Preparation 246 Pyrimidine-5-carboxylic acid methyl ester

[0675] A mixture of 5-bromopyrimidine (3.0 g, 18.8 mmol), 1.86 g of1,1′-bis-(diphenylphospino)ferrocene, and 1.15 g of Pd(II)acetate in 40mL of methanol and 40 mL of N,N-dimethylformamide was stirred under 60psi of carbon monoxide at 85° C. for 16 hours. The reaction mixture wasfiltered and partitioned between ether and brine. The aqueous layer wasextracted with ether. Combined organics were washed with brine, driedover sodium sulfate and was concentrated to dryness. The residue wasdissolved in chloroform, filtered through celite and concentrated todryness to yield 1.89 g (73%) of the desired crude product as a tansolid. Crude product was carried on without further purification. MS(ion spray) 123.3 (M-methyl).

Preparation 247 Pyrimidine-5-carboxylic acid

[0676] To a solution of a compound from preparation 246, 1.8 g (13.0mmol) in 60 mL of tetrahydrofuran, was added a solution of 3.0 g (130mmol) of lithium hydroxide in 60 mL of water. The reaction mixture wasstirred for five hours at ambient temperature and was then washed withether and acidified to pH=1 with 5 N HCl. The resulting solution wasextracted with 20% isopropanol/chloroform. Combined organics were washedwith brine, dried over sodium sulfate, filtered and concentrated todryness to yield 460 mg (28%) of the desired product as a crude tan oil.Crude product was carried on without further purification. MS (ionspray) 123.3 (M−) for desired product.

Preparation 248 2-Methoxyisonicotinic acid methyl ester

[0677] To a solution of 2-methoxyisonicotinic acid methyl ester, 0.32 g(1.9 mmol) in 20 mL of tetrahydrofuran was added 1.9 mL (9.5 mmol) of 5N sodium hydroxide in 10 mL of water. The reaction mixture was stirredfor 2.5 hours at ambient temperature, acidified to pH=3.6 with 5 N HCland concentrated to dryness. The residue was slurried in 20%isopropanol/chloroform and filtered. The solid was slurried in ethylacetate and filtered. The combined organics were dried over sodiumsulfate, filtered and concentrated to dryness to give a quantitativeyield of the crude desired product as a white solid. MS (ion spray)154.1 (M+). Crude product was carried on without further purification.

Preparation 249 2-Cyano-4-methoxypyridine

[0678] To a slurry of 4-methoxypyridine N-oxide hydrate, 50 g, in 250 mLof chloroform was added 20 g of magnesium sulfate. The slurry wasstirred for 1 hour at ambient temperature, then filtered andconcentrated to dryness. To a solution of the residue, 4-methoxypyridineN-oxide, 43 g (350 mmol) in 350 mL of dichloromethane was added 65 mL(490 mmol) of trimethylsilylcyanide. The solution was cooled to 10° C.and 45 mL (490 mmol) of N,N-dimethylcarbamyl chloride was added dropwisesuch that the reaction warmed to a gentle reflux. Upon completion of theaddition, the reaction mixture was stirred overnight at ambienttemperature, then carefully quenched at 0° C. dropwise with 10% aqueouspotassium carbonate. The layers were separated and the aqueous layer wasextracted with dichloromethane. The combined organics were washed withbrine, dried over sodium sulfate, filtered and concentrated to dryness.The residue was triturated with ether. Filtration of the solid provided31.4 g (67%) of the desired product as a white solid. ¹H-NMR isconsistent with structure; MS (ion spray) 135.1 (M+).

Preparation 250 4-Methoxypicolinic acid hydrochloride

[0679] A solution of a compound from preparation 249, 15.0 g (112 mmol)in 100 mL of 5 N HCl was refluxed overnight, cooled to ambienttemperature and concentrated to dryness to yield 22 g the desiredproduct as a crude, white solid. MS (ion spray) 153.9 (M+). Crudeproduct was carried on without further purification.

Preparation 251 6-Methoxynicotinic acid

[0680] To a solution of methyl 6-methoxynicotinate (Avacado), 0.1 g (0.6mmol) in 5 mL of tetrahydrofuran was added a solution of 1.2 mL of 5 Nsodium hydroxide in 5 mL of water. The mixture was stirred for fourhours at ambient temperature, acidified to pH=3 with 5 N HCl andconcentrated to dryness to yield the crude desired compound. MS (ionspray) 154.0 (M+1). The crude product was carried on without furtherpurification.

Preparation 252 Dimethylaminophenylacetic acid methyl ester

[0681] To a solution of α-bromophenylacetic acid methyl ester, 5.0 g(22.0 mmol) in 120 mL of tetrahydrofuran was added 12 mL (88.0 mmol) oftriethylamine and 5.4 g (66.0 mmol) of dimethylamine hydrochloride. Thereaction mixture was heated at 60° C. in a sealed tube for three hours,cooled to ambient temperature and concentrated to dryness. The residuewas partitioned between 20% isopropanol/chloroform and water. Themixture was washed with saturated sodium bicarbonate, washed with brine,dried over sodium sulfate, filtered and concentrated to dryness. Theresidue was purified by chromatography using a methanol/chloroformgradient as eluent and concentrated to dryness to yield 1.86 g (44%) ofthe desired isomer as a yellow oil. MS (ion spray) 193.9 (M+).

Preparation 253 Dimethylaminophenylacetic acid

[0682] To a solution of a compound from preparation 252, 60 mg (0.84mmol) in 10 mL J: of tetrahydrofuran was added a solution of 0.5 mL(2.52 mmol) of 5 N sodium hydroxide in 5 mL of water. The mixture wasstirred for two hours at ambient temperature then an additional 1 mL(5.04 mmol) of 5 N sodium hydroxide was added. The reaction mixture wasstirred an additional four hours, acidified to pH=3 with 5 N HCl, andconcentrated to dryness to give a quantitative yield of the crudedesired mixture of isomers. Crude product was carried on without furtherpurification. MS (ion spray) 202.1 (M+23(Na)).

Preparation 254 Phenylthiomorpholin-4-ylacetic acid methyl ester

[0683] To a solution of racemic α-bromophenylacetic acid methyl ester,5.0 g (22.0 mmol) in 120 mL of tetrahydrofuran was added 3.4 mL (22.0mmol) of triethylamine and 6.7 g (66.0 mmol) of thiomorpholine. Thereaction mixture was refluxed for four hours, cooled to ambienttemperature and concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and water. The mixture was washedwith saturated sodium bicarbonate, washed with brine, dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography using a methanol/chloroform gradient as eluent. Asecond purification was performed using chloroform as eluent and wasconcentrated to dryness to yield 5.36 g (97%) of the desired mixture ofisomers as a yellow oil. MS (ion spray) 252.1 (M+).

Preparation 255 Phenylthiomorpholin-4-ylacetic acid

[0684] To a solution of a compound from preparation 254, 140 mg (0.56mmol) in 5 mL of tetrahydrofuran was added a solution of 0.6 mL (2.8mmol) of 5 N sodium hydroxide in mL of water. The mixture was stirredfor two hours at ambient temperature then an additional 0.5 mL (2.3mmol) of 5 N sodium hydroxide was added in mL of water. The reactionmixture was stirred an additional two hours, acidified to pH=3 with 5 NHCl, and concentrated to dryness to give a quantitative yield of thecrude desired mixture of isomers. Crude product was carried on withoutfurther purification. MS (ion spray) 236.1 (M+23(Na)).

Preparation 256 (4-Methylpiperazin-1-yl)phenylacetic acid methyl ester

[0685] To a solution of racemic α-bromophenylacetic acid methyl ester,5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0mmol) of triethylamine and 7.3 g (66.0 mmol) of 1-methylpiperazine. Thereaction mixture was refluxed for three hours, cooled to ambienttemperature and concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and water. The mixture was washedwith saturated sodium bicarbonate, washed with brine, dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography using methanol/chloroform gradient as eluent. A secondpurification was performed using methanol/chloroform as eluent and wasconcentrated to dryness to yield 5.21 g (95%) of the desired mixture ofisomers as a yellow oil. MS (ion spray) 249.1 (M+).

Preparation 257 (4-Methylpiperazin-1-yl)phenylacetic acid

[0686] To a solution of racemic a compound from preparation 256, 200 mg(0.84 mmol) in 10 mL of dioxane was added a solution of 200 mg (8.4mmol) of lithium hydroxide 8 mL of water. The mixture was stirred forsix hours at ambient temperature, was acidified to pH=3 with 5 N HCl,and concentrated to dryness to give a quantitative yield of the crudedesired mixture of isomers. Crude product was carried on without furtherpurification.

[0687] MS (ion spray) 235.14 (M+).

Preparation 258 (4-Acetylpiperazin-1-yl)phenylacetic acid methyl ester

[0688] To a solution of racemic α-bromophenylacetic acid methyl ester,5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0mmol) of triethylamine and 8.5 g (66.0 mmol) of 1-acetylpiperazine. Thereaction mixture was refluxed for three hours, cooled to ambienttemperature and concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and water. The mixture was washedwith saturated sodium bicarbonate, washed with brine, dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography using a methanol/chloroform gradient as eluent and wasconcentrated to dryness to give a quantitative yield of the desiredmixture of isomers as a yellow, viscous oil. MS (ion spray) 277.2 (M+).

Preparation 259 (4-Acetylpiperazin-1-yl)phenylacetic acid

[0689] To a solution of a racemic compound from preparation 258, 232 mg(0.84 mmol) in 10 mL of dioxane was added a solution of 200 mg (8.4mmol) of lithium hydroxide 8 mL of water. The mixture was stirred forsix hours at ambient temperature, was acidified to pH=3 with 5 N HCl,and concentrated to dryness to give a quantitative yield of the crudedesired mixture of isomers. Crude product was carried on without furtherpurification.

[0690] MS (ion spray) 269.2 (M+Li).

Preparation 259 (Indan-2-ylamino)phenylacetic acid methyl ester

[0691] To a solution of racemic α-bromophenylacetic acid methyl ester,5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0mmol) of triethylamine and 8.8 g (66.0 mmol) of 2-aminoindan. Thereaction mixture was refluxed for four hours, cooled to ambienttemperature and concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and water. The mixture was washedwith saturated sodium bicarbonate, washed with brine, dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby chromatography using chloroform as eluent and was concentrated todryness to give a quantitative yield of the desired mixture of isomersas a tan, viscous oil. MS (ion spray) 282.2 (M+).

Preparation 260 (Indan-2-ylamino)phenylacetic acid

[0692] To a solution of a racemic compound from preparation 259,236 mg(0.84 mmol) in 10 mL of dioxane was added a solution of 200 mg (8.4mmol) of lithium hydroxide 8 mL of water. The mixture was stirred forfour hours at ambient temperature, was acidified to pH=3 with 5 N HCl,and concentrated to dryness to give a quantitative yield of the crudedesired mixture of isomers. Crude product was carried on without furtherpurification. MS (ion spray) 268.2 (M+1).

Preparation 261 Hydroxy-m-tolyl-acetic acid

[0693] To m-methylbenzaldhyde, 21 mL (176 mmol) was added 5 mg of zinc(II) iodide and 23.4 mL (176 mmol) of trimethylsilyl cyanide dropwise.The resulting solution was stirred overnight at ambient temperature. Tothis solution was added 75 mL of 9 N hydrochloric acid. The mixture wasstirred overnight at ambient temperature and was concentrated todryness. The residue was partitioned between water and 20%isopropanol/chloroform and washed with brine, dried over sodium sulfate,filtered and concentrated to dryness. Crude product was recrystallizedfrom chloroform to provide 15 g of a tan solid. NMR analysis indicates a2:1 mixture of product to cyanohydrin intermediate. This mixture wascarried on as is without further purification. MS (ion spray) 165.1(M−1).

Preparation 262 (2-Fluoro-phenyl)-hydroxy-acetic acid

[0694] To o-fluorobenzaldhyde, 18.5 mL (176 mmol) was added 5 mg of zinc(1 l) iodide and 23.4 mL (176 mmol) of trimethylsilyl cyanide dropwise.The resulting solution was stirred overnight at ambient temperature. Tothis solution was added 100 mL of 9 N hydrochloric acid. The mixture wasstirred overnight at ambient temperature, then refluxed overnight. Themixture was then concentrated to dryness. The residue was partitionedbetween water and 20% isopropanol/chloroform and washed with brine,dried over sodium sulfate, filtered and concentrated to dryness. Crudeproduct was recrystallized from chloroform to provide 4.57 g (15%) of atan solid. MS (ion spray) 169.2 (M−).

Preparation 263[3-(3-Acetyl-4-amino-5-chloro-2-oxo-2H-quinolin-1-yl)-cyclohexylmethyl]-carbamicacid benzyl ester

[0695] A solution of[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]arbamicacid benzyl ester (0.5 g, 1.04 mmol) and Mo(CO)₆ (3.0 g, 0.01 mmol) inAcetonitrile (50 mL) and water (5 mL) was heated to 60° C. and stirredovernight. The reaction was concentrated to a solid, diluted in CH₂Cl₂and filtered through Celite to remove the black insoluble material. Thefiltrate was concentrated to a solid and purified using silica gelcolumn chromatography. The product was eluted with 10% EtOAc in CH₂Cl₂.The solvent was removed to afford 0.520 g (quantitative) of product as alight brown oil. MS (ES+) m/z 482.0 (M+H)⁺,(ES−) m/z 479.9 (M−H)⁻, 540.0(M+CH3COO⁻)⁻.

Preparation 264N-[3-(3-Acetyl-4-amino-5-chloro-2-oxo-2H-quinolin-1-yl)-cyclohexylmethyl]-6-fluoronicotinamide

[0696] A solution of Example 420 (0.07 g, 0.15 mmol) and Mo(CO)₆ (0.43g, 1.6 mmol) in Acetonitrile (5 mL) and water (1 mL) was heated to 60°C. and stirred overnight. The reaction was concentrated to a solid,diluted in CHCl₃ and filtered through Celite to remove the blackinsoluble material. The filtrate was concentrated to a solid andpurified using silica gel column chromatography. The product was elutedwith 80% EtOAc in CHCl₃. The solvent was removed to afford 0.04 g (57%)of product as a white solid. MS ES+) m/z 471.1 (M+H)⁺,(ES−) m/z 469.1(M−H)⁻, 529.1 (M+CH₃COO⁻)⁻.

Preparation 265 (2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazolecarboxylicacid ethyl ester

[0697] To a mixture of ethyl3-(2-fluoro-6-iodo-phenyl)-5-methyl-isoxazole carboxylate (0.25 g, 0.67mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.067 mmol), andtriethylamine (5 ml) under N₂ was added trimethylsilyl cyanide andheated at reflux overnight. The reaction was cooled to room temperature,diluted with H₂O, and extracted with EtOAc (2×). The combined extractswere washed (H₂O then brine), dried (MgSO₄), filtered, and concentrated.Flash chromatography (silica gel, EtOAc/hexanes gradient) gave the titlecompound (0.15 g, 82%). Mass Spectrum (ES+) (m/z) 275.0 [M+1].

Preparation 266 3-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazolecarboxylicacid

[0698] A mixture of a compound from preparation 265 (0.14 g, 0.51 mmol),EtOH (2.5 ml), and 5 N NaOH (0.3 ml, 1.5 mmol) was heated at 50° C. for1.5 h. The reaction was cooled to room temperature, diluted with H₂O,and acidified (conc. HCl) to less than pH 3. The mixture was extractedwith EtOAc (2×) and the combined extracts were washed (H₂O then brine),dried (MgSO₄), filtered, and concentrated to give the title compound(0.1 g, 80%). This material was used without further purification. MassSpectrum (ES+) (m/z) 247.0 [M+1].

Preparation 267[3-(2-cyano-6-fluorophenyl)-5-methylisoxazolyl])-N-{3-[(phenylcarbonylamino)-methyl]cyclohexyl}carboxamide

[0699] To a solution of a compound from preparation 265 (0.1 g, 0.41mmol) in dichloromethane (10 ml) under N₂ was added oxalyl chloride(0.07 ml, 0.82 mmol) then DMF (1 drop) and stirred for 2 h. The solutionwas concentrated, redissolved in dichloromethane (5 ml) under N₂, andN-(3-Amino-cyclohexylmethyl)-benzamide (0.114 g, 0.49 mmol) was added.The reaction vessel was submerged in a water bath and triethylamine(0.17 ml, 1.23 mmol) was added dropwise. After 2.5 h of stirring, themixture was diluted with CH₂Cl₂, washed (1.0 NaOH then brine), dried(MgSO₄), filtered, and concentrated. Flash chromatography (silica gel,Acetone/CH₂Cl₂ gradient) gave the title compound (0.119 g, 63%). MassSpectrum (ES+) (m/z) 461.2 [M+1].

Preparation 268 (3-Amino-cyclohexylmethyl)-carbamic acid benzyl ester

[0700] A solution of[3-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butylester (6 g, 16.6 mmol) in TFA (30 ml) was stirred for 1.5 h. Thesolution was concentrated using benzene to azeotrope, diluted withEtOAc, washed (1.0 N NaOH), dried (Na₂SO₄), filtered, and concentratedto afford the title compound (4.2 g, 97%) as a crude solid. MassSpectrum (ES+) (m/z) 263.1 [M+1].

Preparation 269(3-{[3-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)-carbamicacid benzyl ester

[0701] In a fashion similar to that described for preparation 267, acompound from preparation 266 (3.05 g, 12.4 mmol), oxalyl chloride (2.16ml, 24.8 mmol), dichloromethane (50 ml), DMP (0.05 ml), a compound frompreparation 268 (4.2 g, 16.1 mmol), dichloromethane (125 ml), andtriethylamine (5.17 ml, 37.2 mmol) gave the title compound (4.6 g, 76%)after flash chromatography (silica gel, acetone/CH2Cl2 gradient). MassSpectrum (ES+) (m/z) 491.2 [M+1].

Preparation 270 Diphenylmethyl 2-(3-oxocyclohexyl)propane-1,3-dioate(cis racemic)

[0702] To a solution of LiAlH₄ (6 ml, 6 mmol) under N₂ at 0° C. wasadded a solution of (S)-1,1′-binaphthol (3.43 g, 12 mmol) in THF (48 ml)and stirred for 30 min. The reaction was warmed to RT. To this was addeda solution of sodium salt benzyl malonate in THE which was prepared byreacting benzyl malonate (14.99 ml, 60 mmol), NaH (60% by wt., 0.216 g,5.4 mmol), and THF (60 ml) until all bubbling ceased. Next,cyclohexenone (5.82 ml, 60 mmol) and dibenzlmalonate (1.35 ml, 5.4 mmol)were added and the reaction mixture was stirred overnight. 1.0 N HCl wasadded and extracted with EtOAc (3×). The combined EtOAc layers werewashed (brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (silica gel, acetone/hexanes gradient) gave the titlecompound (16.17 g, 71%). Mass Spectrum (FIA) (m/z) 381.3 [M+1].

Preparation 271 Diphenylmethyl 2-(3-oxocyclohexyl)propane-1,3-dioate(trans racemic)

[0703] To a −78° C. solution of a compound from preparation 270 (seeArai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem.Eur. J. 1996, 2, 1368-1372.) (16.15 g, 42.5 mmol) in THF (212.5 ml)under N₂ was added L-selectride (46.75 ml at 1.0 M, 46.75 mmol) dropwiseand the mixture was stirred for 3.5 h at −78° C. EtOAc and H₂O wereadded and the mixture was warmed to room temperature. Dilution with moreEtOAc followed by washing with 1N NaOH, saturated NH₄Cl, brine, drying(MgSO₄), and flash chromatography (silica gel, EtOAc/hexanes gradient)gave the title compound(14.29 g, 88%). Mass Spectrum (FIA) (m/z) 383.3[M+1].

Preparation 272 Phenylmethyl 2-(3-hydroxycyclohexyl)acetate (transracemic)

[0704] A solution of a compound from preparation 271 (19.19 g, 50.2mmol, LiCl (4.27 g, 100.5 mmol, H₂O (1.81 ml, 100.5 mmol), and DMSO (135ml) was lowered into a 165° C. oil bath for 2 h then heated at 175° C.for 1.5 h. The reaction was cooled to room temperature and diluted withEtOAc. Washing with H₂O and brine, drying (MgSO₄), and flashchromatography (silica gel, EtOAc/hexanes gradient) gave the titlecompound (9.71 g, 78%). ¹H NMR: consistent with structure.

Preparation 273 Phenylmethyl 2-(3-azidocyclohexyl)acetate (cis racemic)

[0705] To a solution of a compound from preparation 272 (9.71 g, 39.2mmol), triphenylphosphine (12.32 g, 41.04 mmol), and hydrazoic acid(30.9 ml, at 1.9 M, 58.7 mmol) in toluene (120 ml) was added DEAD (9.24ml, 58.7 mmol) dropwise and stirred for 72 h. The mixture was dilutedwith EtOAc, washed with 0.1 N NaOH, H₂O, and brine, dried (MgSO₄), andchromatographed (silica gel, CH₂Cl₂/hexanes gradient) to give the titlecompound (10.0 g, 93%). 1H NMR: consistent with structure.

Preparation 274 Phenylmethyl2-{3-[(tert-butoxy)carbonylamino]cyclohexyl}acetate (cis racemic)

[0706] A mixture of a compound from preparation 273 (10 g, 36.6 mmol),(BOC)₂O (9.57 g, 43.9 mmol), Lindlar's catalyst (3.7 g), and EtOAc (200ml) was stirred under an atmosphere of hydrogen gas (balloon) for 24 h,filtered through celite, and concentrated. Flash chromatography (silicagel, EtOAc/hexanes gradient) gave the title compound (7.03 g, 55%). MassSpectrum (FD+) (m/z) 347.3 [M⁺].

Preparation 275 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic acid(cis racemic)

[0707] In a fashion similar to that described for preparation 266, acompound from preparation 274 (7 g, 20.2 mmol), 2 N NaOH (25 ml, 50mmol), Dioxane (100 ml) were reacted for 5 h to give the title compound(5.2 g, 100%). Mass Spectrum (FD+) (m/z) 257.3 [M⁺].

Preparation 276(t-Butoxy)-N-(3-{[(phenylmethoxy)carbonylaiino]methyl}cyclohexyl)carboxamide(cis racemic)

[0708] To a solution of a compound from preparation 275 (2.6 g, 10.1mmol), Et₃N (2.84 ml, 20.4 mmol) in toluene (100 ml) under N₂ was addedDPPA (4.39 ml, 20.4 mmol) and benzyl alcohol (3.13 ml, 30.3 mmol). Thesolution was heated to reflux overnight. The reaction was cooled to roomtemperature, diluted with EtOAc, washed (1.0 N NaOH then brine), dried(MgSO₄), filtered, and concentrated. Flash chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (2.92 g, 80%). ¹H NMR:consistent with structure.

Preparation 277 N-[3-(Aminomethyl)cyclohexyl](t-butoxy)carboxamide (cisracemic)

[0709] A mixture of a compound from preparation 276 (1 g, 2.76 mmol),10% Pd/C catalyst (0.5 g), and EtOAc (30 ml) was stirred under anatmosphere of hydrogen gas (balloon) for 18 h, filtered through celite,and concentrated to give the title compound (0.48 g, 76%), which wastaken on without further purification. Mass Spectrum (ES+) (m/z) 229.1[M+1].

Preparation 278N-({3-[(t-Butoxy)carbonylamino]cyclohexyl}methyl)[3-(6-chloro-2-fluorophenyl)-5-methylisoxazolyl]carboxamide

[0710] To a solution of a compound from preparation 277 (0.48 g, 2.1mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonylchloride (0.75 g, 2.74 mmol) in dichloromethane (20 ml) under N₂ wasadded dropwise triethylamine (0.73 ml, 5.25 mmol) and stirred for 4 h.The reaction was diluted with dichloromethane, washed (H₂O then brine),dried (MgSO₄), filtered, and concentrated. Flash chromatography (silicagel, hexanes/EtOAc gradient) gave the title compound (0.726 g, 74%).Mass Spectrum (ES+) (m/z) 366.1 [M−BOC].

Preparation 279[5-chloro-3-(6-chloro-2-fluorophenyl)isoxazol-4-yl]-N-{3-[(phenylcarbonylamino)-methyl]cyclohexyl}carboxamide

[0711] In a fashion similar to that described for preparation 267,4-carboxy-5-chloro-3-(2-chloro-5-fluorophenyl)isoxazole acid (0.22 g,0.84 mmol), dichloromethane (2 ml), oxalyl chloride (0.15 ml, 1.68mmol), DMF (0.01 ml), dichloromethane (5 ml),N-(3-Amino-cyclohexylmethyl)-benzamide (0.15 g, 0.65 mmol), andtriethylamine (0.35 ml, 2.52 mmol) gave the title compound (0.29 g, 90%)after flash chromatography (silica gel, Acetone/CH₂Cl₂ gradient). MassSpectrum (ES+) (m/z) 490.1 [M+1].

Preparation 280[5-Diethylamino)-3-(6-chloro-2-fluorophenyl)isoxazolfyl]-N-{3-[(phenylcarbonylamino)methyl]cyclohexyl}carboxamide

[0712] To a solution of a compound from preparation 278 (0.1 g, 0.2mmol) in DMF (2.5 ml) under N₂ was added diethylamine (0.065 ml, 0.63mmol)_(j) and stirred for 2 h. The reaction was diluted with EtOAc,washed (H₂O then brine), dried (MgSO₄), filtered, and concentrated. (0.1N HCl and brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (silica gel, acetone/CH₂Cl₂ gradient) gave the titlecompound (0.1 g, 93%). Mass Spectrum (ES+) (m/z) 527.2 [M+1].

Preparation 281[3-(6-Chloro-2-fluorophenyl)-5-pyrTrolidinylisoxazolyl]-N-{3-[(phenylcarbonylamino)methyl]cyclobexyl}carboxamide

[0713] In a fashion similar to that described for preparation 280, acompound from preparation 279 (0.085 g, 0.17 mmol), DMF (2.5 ml),pyrrolidine (0.14 ml, 1.7 mmol) gave the title compound (0.089 g, 100%)which was taken on as a crude residue. Mass Spectrum (ES+) (m/z) 525.2[M+1].

Preparation 282[3-(6-Chloro-2-fluorophenyl)-5-(ethylamino)isoxazolyl-4-yl]-N-{3-[(phenylcarbonyl-amino)methyl]cyclohexyl}carboxamide

[0714] In a fashion similar to that described for preparation 280, acompound from preparation 61 (0.085 g, 0.17 mmol), DMF (2.5 ml),ethylamine (0.85 ml, 1.7 mmol) gave the title compound (0.085 g, 100%)which was taken on as a crude residue. Mass Spectrum (ES+) (m/z) 499.2[M+1].

Preparation 283[3-(6-Chloro-2-fluorophenyl)-5-ethylthioisoxazolyl]-N-{3-[(phenylcarbonyl-amino)methyl]cyclohexyl}carboxamide

[0715] In a fashion similar to that described for preparation 280, acompound from preparation 279 (0.1 g, 0.2 mmol), DMF (2.5 ml), sodiumethanethiolate (0.103 g, 1.0 mmol) gave the tide compound (0.85 g, 100%)which was taken on as a crude residue. ¹H NMR: consistent withstructure.

Preparation 284 4-(Methoxycarbonyl-phenyl-methyl)piperazine-1-carboxylicacid tert-butyl ester

[0716] To a solution of racemic α-bromophenylacetic acid methyl ester,5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0mmol) of Et₃N and 12.3 g (66.0 mmol) of BOC-piperazine. The reactionmixture was refluxed for 3.5 hours, cooled to rt. and concentrated todryness. The residue was partitioned between 20% isopropanol/chloroformand water. The mixture was washed with saturated NaHCO₃, washed withbrine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by chromatography using chloroform as eluent andwas concentrated to dryness to yield 7.73 g (100% o) of the desiredmixture of isomers as a colorless oil. MS (ion spray) 335.2 (M+).

Preparation 285 4-(Carboxy-phenyl-methyl)-piperazine-1-carboxylic acidtert-butyl ester

[0717] To a solution of the compound from preparation 284, 560 mg (1.68mmol) in 15 mL of dioxane was added a solution of 400 mg (16.8 mmol) oflithium hydroxide in 15 mL of water. The solution was stirred for fivehours at rt. then acidified to pH=3.0 with 5 N HCl and concentrated todryness to give a quantitative yield of the crude desired mixture ofisomers. MS (ion spray) 319.2 (M−). Crude product was carried on withoutfurther purification.

Preparation 286 [4(2-Hydroxy-ethyl)-piperazin-1-yl]-phenyl-acetic acidmethyl ester

[0718] To a solution of racemic α-bromophenylacetic acid methyl ester,5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0mmol) of Et₃N and 8 mL (66.0 mmol) of 1-(hydroxyethyl)piperazine. Thereaction mixture was refluxed for three hours, cooled to rt. andconcentrated to dryness. The residue was partitioned between 20%isopropanol/chloroform and water. The mixture was washed with saturatedNaHCO₃, washed with brine, dried over Na₂SO₄, filtered and concentratedto dryness to give a quantitative yield of the desired mixture ofisomers as a yellow oil. MS (ion spray) 279.1 (M+).

Preparation 287 [4-(2-Hydroxy-ethyl)-piperazin-1-yl]-phenyl-acetic acid

[0719] To a solution of the compound from preparation 286, 470 mg (1.68mmol) in 20 mL of dioxane was added a solution of 400 mg (16.8 mmol) oflithium hydroxide in 20 mL of water. The solution was stirred for 2.5hours at rt. then acidified to pH=3.0 with 5 N HCl and concentrated todryness to give a quantitative yield of the crude desired mixture ofisomers. Crude product was carried on without further purification. MS(ion spray) 319.2 (M−).

Preparation 288 Phenyl-(4-pyridin-2-yl-piperazin-1-yl)-acetic acidmethyl ester

[0720] To a solution of racemic α-bromophenylacetic acid methyl ester,5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0mmol) of Et₃N and 10 mL (66.0 mmol) of 1-(2-pyridyl)-piperazine. Thereaction mixture was refluxed for five hours, cooled to rt. andconcentrated to dryness. The residue was partitioned between 20%isopropanol/chloroform and water. The mixture was washed with saturatedNaHCO₃, washed with brine, dried over Na₂SO₄, filtered and concentratedto dryness. The residue was purified by column chromatography usingMeOH/chloroform as eluant and concentrated to dryness to give aquantitative yield of the desired mixture of isomers as a yellow oil. MS(ion spray) 312.2 (M+).

Preparation 289 Piperidin-1-yl-acetic acid ethyl ester

[0721] To a solution of bromoethylacetate, 3.3 g (30.0 mmol) in 100 mLof tetrahydrofuran was added 4.2 mL (30.0 mmol) of Et₃N and 9 mL (90.0mmol) of piperidine. The reaction mixture stirred overnight at rt. andwas concentrated to dryness. The residue was partitioned betweenchloroform and saturated aqueous NaHCO₃. The mixture was washed withsaturated NaHCO₃, washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness to give 4.6 g (89%) of the desired product as atan oil. MS (ion spray) 172.2 (M+).

Preparation 290 Piperidin-1-yl-acetic acid

[0722] To a solution of the compound from preparation 289, 143 mg (0.84mmol) in 5 mL of dioxane was added a solution of 66 mg (8.4 mmol) oflithium hydroxide in 5 mL of water. The solution was stirred for threehours at rt. then acidified to pH=2.0 with 5 N HCl and concentrated todryness to give a quantitative yield of the crude desired product. MS(ion spray) 144.1 (M+). Crude product was carried on without furtherpurification.

Preparation 291 (4-Methyl-piperazin-1-yl)-acetic acid ethyl ester

[0723] To a solution of bromoethylacetate, 3.3 g (30.0 mmol) in 100 mLof tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonateand 3.3 mL (30.0 mmol) of 4-methylpiperazine. The reaction mixturestirred overnight at rt and was concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and saturated aqueousNaHCO₃. The mixture was washed with saturated NaHCO₃, washed with brine,dried over Na₂SO₄, filtered and concentrated to dryness to give 1.23 g(22%) of the desired product as a tan oil. MS (ion spray) 187.1 (M+).

Preparation 292 (4-Methyl-piperazin-1-yl)acetic acid

[0724] To a solution of the compound from preparation 291, 160 mg (0.84mmol) in 5 mL of dioxane was added a solution of 66 mg (8.4 mmol) oflithium hydroxide in 5 mL of water. The solution was stirred for twohours at rt. then acidified to pH=3.0 with 5 N HCl and concentrated todryness to give a quantitative yield of the crude desired product. MS(ion spray) 159.1 (M+). Crude product was carried on without furtherpurification.

Preparation 293 (Methyl-phenyl-amino)-acetic acid ethyl ester

[0725] To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mLof tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonateand 3.25 mL of N-methylaniline. The reaction mixture stirred overnightat rt. and was concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and saturated aqueous NaHCO₃. Themixture was washed with saturated NaHCO₃, washed with brine, dried overNa₂SO₄, filtered and concentrated to dryness. The residue was purifiedby column chromatography using EtOAc/hexanes as eluent and concentratedto dryness to give 4.74 g (82%) of the desired product as a tan oil. MS(ion spray) 194.1 (M+1).

Preparation 294 Phenyl-(pyridin-3-yloxy)acetic acid methyl ester

[0726] To a slurry of 3-hydroxypyridine sodium salt, 4.6 g (26.4 mmol)in 200 mL of tetrahydrofuran was added 5.0 g (22.0 mmol) ofalpha-bromophenylacetic acid. The reaction mixture was refluxed for twohours, cooled to rt. and concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and water. The mixturewas washed with saturated NaHCO₃, washed with brine, dried over Na₂SO₄,filtered and concentrated to dryness. The residue was purified by columnchromatography using MeOH/chloroform as eluent and concentrated todryness to give 2.8 g of the desired mixture of isomers as a dark oil.MS (ion spray) 244.1 (M+).

Preparation 295 (Pyridin-3-yloxy)acetic acid ethyl ester

[0727] To a solution of 3-hydroxypyridine sodium salt, 6.4 g (36.0 mmol)in 200 mL of DMF was added 3.3 mL (30.0 mmol) of bromoethylacetate. Thereaction mixture stirred overnight at rt. and was concentrated todryness. The residue was partitioned between 20% isopropanol/chloroformand saturated aqueous NaHCO₃. The mixture was washed with saturatedNaHCO₃, washed with brine, dried over Na₂SO₄, filtered and concentratedto dryness. The residue was purified by column chromatography usingMeOH/chloroform as eluent and concentrated to dryness to give 3.8 g(70%) of the desired product as a tan oil. MS (ion spray) 182.1 (M+).

Preparation 296 (Pyridin-3-yloxy)-acetic acid

[0728] To a solution of the compound from preparation 295,(pyridin-3-yloxy)-acetic acid ethyl ester, 300 mg (1.68 mmol) in 15 mLof dioxane was added a solution of 400 mg (16.8 mmol) of lithiumhydroxide in 15 mL of water. The solution was stirred for three hours atrt. then acidified to pH=1.0 with 5 N HCl and concentrated to dryness togive a quantitative yield of the crude desired product. MS (ion spray)154.1 (M+). Crude product was carried on without further purification.

Preparation 297 1-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid

[0729] To a slurry of 1-amino-1-cyclohexane-carboxylic acid, 5.0 g (35.0mmol) in 50 mL of tetrahydrofuran and 50 mL of water was added 14.5 g(105.0 mmol) of potassium carbonate, 7.7 g (35.0 mmol) of BOC-anhydrideand 5 mg of DMAP. The mixture was stirred overnight at rt. and theorganics were evaporated off in vacuo. The aqueous layer was acidifiedto pH=1 with 5 N HCl and extracted with 20% isopropanol/chloroform. Thecombined organics were washed with brine, dried over Na₂SO₄, filteredand concentrated to dryness to yield 1.83 g (21%) of the desired productas a white oil that solidifies upon standing. MS (IS) 244.2 (M+).

Preparation 298 Morpholin-4-yl-acetic acid ethyl ester

[0730] To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mLof tetrahydrofuran was added 4.14 g (30.0 mmol) of potassium carbonateand 2.6 mL (30.0 mmol) of morpholine. The reaction mixture stirredovernight at rt. and was concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and saturated aqueousNaHCO₃. The mixture was washed with saturated NaHCO₃, washed with brine,dried over Na₂SO₄, filtered and concentrated to dryness to give 2.75 g(53%) of the desired product as a tan oil. MS (ion spray) 174.2 (M+).

Preparation 299 Morpholinyl-acetic acid

[0731] To a solution of the compound from preparation 298, 150 mg (0.84mmol) in 10 mL of dioxane was added a solution of 198 mg (8.4 mmol) oflithium hydroxide in 10 mL of water. The solution was stirred for twohours at rt. then acidified to pH=2.0 with 5 N HCl and concentrated todryness to give a quantitative yield of the crude desired product MS(ion spray) 146.0 (M+). Crude product was carried on without furtherpurification.

Preparation 300 (4-Hydroxy-piperidin-1-yl)-acetic acid ethyl ester

[0732] To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mLof tetrahydrofuran was added 4.2 g (30.0 mmol) of potassium carbonateand 3.0 mL (30.0 mmol) of 4-hydroxypiperidine. The reaction mixturestirred overnight at rt. and was concentrated to dryness. The residuewas partitioned between 20% isopropanol/chloroform and saturated aqueousNaHCO₃. The mixture was washed with saturated NaHCO₃, washed with brine,dried over Na₂SO₄, filtered and concentrated to dryness to give 4.65 g(83%) of the desired product as a tan oil. MS (ion spray) 188.0 (M+).

Preparation 301 (4-Hydroxy-piperidin-1-yl)acetic acid

[0733] To a solution of the compound from preparation 300, 158 mg (0.84mmol) in 10 mL of dioxane was added a solution of 198 mg (8.4 mmol) oflithium hydroxide in 10 mL of water. The solution was stirred for 1.5hours at rt then acidified to pH=2.0 with 5 N HCl and concentrated todryness to give a quantitative yield of the crude desired product. MS(ion spray) 160.1 (M+). Crude product was carried on without furtherpurification.

Preparation 302 (2-Oxo-2H-pyridin-1-yl)-acetic acid ethyl ester

[0734] To a slurry of sodium hydride, 1.73 g (43.2 mmol) in 100 mL ofDMF was added 3.4 g (36.0 mmol) of 2-hydroxypyridine. The mixture wasstirred 10 minutes then added to a solution of 3.3 mL (30.0 mmol) ofbromoethylacetate in 100 mL DMF. The reaction mixture was stirred 72hours at rt. then concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and water and washed with saturatedaqueous NaHCO₃, washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by columnchromatography using MeOH/chloroform as eluent and concentrated todryness to yield 3.52 g (65%) of the desired product as a colorless oil.¹H-NMR is consistent with structure. MS (ion spray) 182.1 (M+).

Preparation 303 (2-Oxo-2H-pyridin-1-yl)acetic acid

[0735] To a solution of the compound from preparation 302, 152 mg (0.84mmol) in 10 mL of dioxane was added a solution of 198 mg (8.4 mmol) oflithium hydroxide in 10 mL of water. The solution was stirred for twohours at rt. then acidified to pH=1.0 with 5 N HCl and concentrated todryness to give a quantitative yield of the crude desired product. MS(ion spray) 154.1 (M+). Crude product was carried on without furtherpurification.

Preparation 304 (Pyridin-4-yloxy)acetic acid ethyl ester

[0736] To a slurry of sodium hydride, 1.73 g (43.2 mmol) in 100 mL ofDMF was added 3.4 g (36.0 mmol) of 4-hydroxypyridine. The mixture wasstirred 10 minutes then added to a solution of 3.3 mL (30.0 mmol) ofbromoethylacetate in 100 mL DMF. The reaction mixture was stirred 72hours at rt. then concentrated to dryness. The residue was partitionedbetween 20% isopropanol/chloroform and water and washed with saturatedaqueous NaHCO₃, washed with brine, dried over Na₂SO₄, filtered andconcentrated to dryness. The residue was purified by radialchromatography using MeOH/chloroform as eluent and concentrated todryness to yield 510 mg (9.4%) of the desired product as a tan oil.¹H-NMR is consistent with structure. MS (ion spray) 182.1 (M+).

Preparation 305 tert-Butylamino-acetic acid

[0737] To a solution of tert-Butyl amino-acetic acid methyl ester(Maybridge), 122 mg (0.84 mmol) in 10 mL of dioxane was added a solutionof 60 mg (2.52 mmol) of lithium hydroxide in 10 mL of water. Thereaction mixture was stirred for two hours, acidified to pH=1 with 5 NHCl and concentrated to dryness to yield the crude desired product whichwas carried on without further purification. MS (IS) 132.1 (M+1).

Preparation 306 (6-Methoxy-pyridin-3-ylamino)-acetic acid

[0738] To a solution of (6-methoxy-pyridin-3-ylamino)-acetic acid methylester, 113 mg (0.58 mmol) in 10 mL of dioxane was added a solution of 70mg (2.9 mmol) of lithium hydroxide in 10 mL of water. The reactionmixture was stirred for three hours, acidified to pH=1 with 5 N HCl andconcentrated to dryness to yield the crude desired product which wascarried on without further purification. MS (IS) 183.1 (M+1).

Preparation 307 2-(Pyridin-3-yloxy)-propionic acid

[0739] To a solution of 2-(pyridin-3-yloxy)-propionic acid ethyl ester,320 mg (1.6 mmol) in 10 mL of dioxane was added a solution of 190 mg(8.0 mmol) of lithium hydroxide in 10 mL of water. The reaction mixturewas stirred for three hours, acidified to pH=1 with 5 N HCl andconcentrated to dryness to yield the crude desired product which wascarried on without further purification. MS (IS) 168.1 (M+1).

Preparation 308 1-Benzoyl-pyrrolidine-2-carboxylic acid methyl ester

[0740] Benzoyl chloride (1.40 mL, 12.1 mmol) was added in a dropwisemanner to a mixture of L-proline methyl ester hydrochloride (2.00 g,12.1 mmol) and Et₃N (4.20 mL, 30.2 mmol) in CH₂Cl₂ (40 mL) and theresulting mixture stirred overnight at rt. The mixture was concentratedin vacuo and the residue treated with water and extracted with EtOAc andthe combined extracts dried over Na₂SO₄. Concentration left a residuewhich was loaded onto a silica gel column and eluted with MeOH/CH₂Cl₂which allowed for isolation of 2.76 g (94%) of the title compound as awhite solid. MS(ES): (M+1)+234.2 m/z.

Preparation 309 1-Benzoyl-pyrrolidine-2-carboxylic acid

[0741] The compound from preparation 308 (1.00 g, 4.3 mmol) was combinedwith aqueous 2N sodium hydroxide (4.0 mL, 8.0 mmol), tetrahydrofuran(2.0 mL) and MeOH (2.0 mL) and the mixture stirred at rt. untilhydrolysis was complete. Organic solvents were removed in vacuo and themixture was diluted with water and adjusted to pH 2.0-3.0 with aqueoushydrochloric acid. The mixture was then concentrated to dryness invacuo. The resulting solids were then slurried (and washed) with anEtOAc/ethanol mixture followed by filtration. Concentration of thefiltrate left desired acid of acceptable purity (0.52 g, 55%) as a whitesolid. MS(ES): (M+1)+220.3 m/z.

Preparation 310 1-Phenylacetyl-pyrrolidine-2-carboxylic acid methylester

[0742] Phenacetyl chloride (1.60 mL, 12.1 mmol) was added to a mixtureof L-proline methyl ester hydrochloride (2.00 g, 12.1 mmol) and Et₃N(4.20 mL, 30.2 mmol) in CH₂Cl₂ (40 mL) and the resulting mixture stirredovernight at rt. The mixture was treated in a manner similar to that inpreparation 103, which resulted in recovery of 1.74 g (58%) of thedesired ester as a clear oil. MS(ES): (M+1)⁺ 248.2, 249.2 m/z.

Preparation 311 1-Phenylacetyl-pyrrolidine-2-carboxylic acid

[0743] The compound from preparation 310 (1.00 g, 4.0 mmol) was combinedwith aqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran(2.0 mL) and MeOH (2.0 mL) and the mixture stirred at rt. untilhydrolysis was complete. The mixture was then treated in a mannersimilar to preparation 104, however when the pH was adjusted the desiredacid began to precipitate. Filtration and drying of the precipitatenetted 0.70 g (74%) of the title compound as a white powdery solid.MS(ES): (M+1)+234.3.

Preparation 312 N-Benzyl-L-proline

[0744] N-Benzyl-L-proline ethyl ester (1.00 g, 4.3 mmol) was combinedwith aqueous 2N sodium hydroxide (5.0 mL, 10.0 mmol), tetrahydrofuran(2.0 mL) and MeOH (2.0 mL) and the mixture stirred at rt. untilhydrolysis was complete. The mixture was then treated in a mannersimilar to preparation 104. Concentration of the filtrate netted 0.79 g(90%) of crude acid as a light yellowish solid. MS(ES): (M+1)+206.3,207.3.

Preparation 3143-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethylester

[0745] To a mixture of ethyl3-(2-Fluoro-6-iodo-phenyl)-5-methyl-isoxazole-4 carboxylate (0.25 g,0.67 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.067 mmol),and Et₃N (5 mL) under N₂ was added TMSCN and heated at reflux overnight.The reaction was cooled to room temperature, diluted with H₂O, andextracted with EtOAc (2×). The combined extracts were washed (H₂O thenbrine), dried (MgSO₄), filtered, and concentrated. Flash chromatography(silica gel, EtOAc/hexanes gradient) gave the title compound (0.15 g,82%). Mass Spectrum (S+) (m/z) 275.0 [M+1].

Preparation 3153-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid

[0746] A mixture of a compound from preparation 314, (0.14 g, 0.51mmol), EtOH (2.5 mL), and 5 N NaOH (0.3 mL, 1.5 mmol) was heated at 50°C. for 1.5 h. The reaction was cooled to rt., diluted with H₂O, andacidified (conc. HCl) to less than pH 3. The mixture was extracted withEtOAc (2×) and the combined extracts were washed (H₂O then brine), dried(MgSO₄), filtered, and concentrated to give the title compound (0.1 g,80%). This material was used without further purification. Mass Spectrum(ES+) (m/z) 247.0 [M+].

Preparation 3163-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid[3-(benzoylamino-methyl)-cyclohexyl]-amide

[0747] To a solution of a compound from preparation 315, (0.1 g, 0.41mmol) in CH₂Cl₂ (10 mL) under N₂ was added oxalyl chloride (0.07 mL,0.82 mmol) then DMF (1 drop) and stirred for 2 h. The solution wasconcentrated, redissolved in CH₂Cl₂ (5 mL) under N₂, andN-(3-amino-cyclohexylmethyl)-benzamide (0.114 g, 0.49 mmol) was added.The reaction vessel was submerged in a water bath and Et₃N (0.17 mL,1.23 mmol) was added dropwise. After 2.5 h of stirring, the mixture wasdiluted with CH₂Cl₂, washed (1.0 NaOH then brine), dried (MgSO₄),filtered, and concentrated. Flash chromatography (silica gel,Acetone/CH₂Cl₂ gradient) gave (0.119 g, 63%). Mass Spectrum (ES+) (m/z)461.2 [M+1].

Preparation 317 (3-Amino-cyclohexylmethyl)-carbamic acid benzyl ester

[0748] A solution of[3-(benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamic acid tert-butylester (6 g, 16.6 mmol) in TFA (30 mL) was stirred for 1.5 h. Thesolution was concentrated using benzene to azeotrope, diluted withEtOAc, washed (1.0 N NaOH), dried (Na₂SO₄), filtered, and concentratedto afford (4.2 g, 97%) as a crude solid. Mass Spectrum (ES+) (m/z) 263.1[M+1].

Preparation 318(3-{[3-(2-Cyano-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-cyclohexylmethyl)carbamicacid benzyl ester.

[0749] In a fashion similar to that described for preparation 316, acompound from preparation 315 (3.05 g, 12.4 mmol), oxalyl chloride (2.16mL, 24.8 mmol), CH₂Cl₂ (50 mL), DMF (0.05 mL),(3-amino-cyclohexylmethyl)carbamic acid benzyl ester (4.2 g, 16.1 mmol),CH₂Cl₂ (125 mL), and Et₃N (5.17 mL, 37.2 mmol) gave the title compound(4.6 g, 76%) after flash chromatography (silica gel, acetone/CH₂Cl₂gradient). Mass Spectrum (ES+) (m/z) 491.2 [M+1].

Preparation 319 2-(3-Oxo-cyclohexyl)-malonic acid dibenzyl ester

[0750] To a solution of LiAlH₄ (6 mL, 6 mmol) under N₂ at 0° C. wasadded a solution of (S)-1,1′-binaphthol (3.43 g, 12 mmol) in THF (48 mL)and stirred for 30 min. The reaction was warmed to RT. To this was addeda solution of sodium salt benzyl malonate in THF which was prepared byreacting benzyl malonate (14.99 mL, 60 mmol), NaH (60% by wt., 0.216 g,5.4 mmol), and THF (60 mL) until all bubbling ceased. Next,cyclobexenone (5.82 mL, 60 mmol) and dibenzlmalonate (1.35 mL, 5.4 mmol)were added and the reaction mixture was stirred overnight. 1.0 N HCl wasadded and extracted with EtOAc (3×). The combined EtOAc layers werewashed (brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (silica gel, acetone/hexanes gradient) gave the titlecompound (16.17 g, 71%). Mass Spectrum (FIA) (m/z) 381.3 [M+1].

Preparation 320 2-(3-Hydroxy-cyclohexyl)-malonic acid dibenzyl ester

[0751] To a −78° C. solution of a compound from preparation 319 (seeArai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, R; Shibasaki, M. Chem.Eur. J. 1996, 2, 1368-1372.) (16.15 g, 42.5 mmol) in THF (212.5 mL)under N₂ was added L-selectride (46.75 mL at 1.0 M, 46.75 mmol) dropwiseand the mixture was stirred for 3.5 h at −78° C. EtOAc and H₂O wereadded and the mixture was warmed to rt. Dilution with more EtOAcfollowed by washing with 1N NaOH, saturated NH₄Cl, brine, drying(MgSO₄), and flash chromatography (silica gel, EtOAc/hexanes gradient)gave the title compound (14.29 g, 88%). Mass Spectrum (FIA) (m/z) 383.3[M+1].

Preparation 321 (3-Hydroxy-cyclohexyl)-acetic acid benzyl ester

[0752] A solution of a compound from preparation 320 (19.19 g, 50.2mmol, LiCl (4.27 g, 100.5 mmol, H₂O (1.81 mL., 100.5 mmol), and DMSO(135 mL) was lowered into a 165° C. oil bath for 2 h then heated at 175°C. for 1.5 h. The reaction was cooled to rt. and diluted with EtOAc.Washing with H₂O and brine, drying (MgSO₄), and flash chromatography(silica gel, EtOAc/hexanes gradient) gave the title compound (9.71 g,78%). ¹H NMR: consistent with structure.

Preparation 322 (3-Azido-cyclohexyl)-acetic acid benzyl ester

[0753] To a solution of a compound from preparation 321 (9.71 g, 39.2mmol), Ph₃P (12.32 g, 41.04 mmol), and hydrazoic acid (30.9 mL, at 1.9M, 58.7 mmol) in toluene (120 mL) was added DEAD (9.24 mL, 58.7 mmol)dropwise and stirred for 72 h. The mixture was diluted with EtOAc,washed with 0.1 N NaOH, H₂O, and brine, dried (MgSO₄), andchromatographed (silica gel, CH₂Cl₂/hexanes gradient) to give the titlecompound (10.0 g, 93%). ¹H NMR: consistent with structure.

Preparation 323 (3-tert-Butoxycarbonylamino-cyclohexyl)-acetic acidbenzyl ester

[0754] A mixture of a compound from preparation 322 (10 g, 36.6 mmol),(BOC)₂O (9.57 g, 43.9 mmol), Lindlar's catalyst (3.7 g), and EtOAc (200mL) was stirred under an atmosphere of hydrogen gas (balloon) for 24 h,filtered through celite, and concentrated. Flash chromatography (silicagel, EtOAc/hexanes gradient) gave the title compound (7.03 g, 55%). MassSpectrum (FD+) (m/z) 347.3 [M⁺].

Preparation 324 (3-tert-Butoxycarbonylamino-cyclohexyl)-acetic acid

[0755] In a fashion similar to that described for preparation 315, acompound from 1 preparation 323 (7 g, 20.2 mmol), 2 N NaOH (25 mL, 50mmol), Dioxane (100 mL) were reacted for 5 h to give the title compound(5.2 g, 100%). Mass Spectrum (FD+) (m/z) 257.3 [M+].

Preparation 325 [3-(Benzyloxycarbonylamino-methyl)-cyclohexyl]-carbamicacid tert-butyl ester

[0756] To a solution of a compound from preparation 324 (2.6 g, 10.1mmol), Et₃N (2.84 mL, 20.4 mmol) in toluene (100 mL) under N₂ was addedDPPA (4.39 mL, 20.4 mmol) and benzyl alcohol (3.13 mL, 30.3 mmol). Thesolution was heated to reflux overnight. The reaction was cooled to roomtemperature, diluted with EtOAc, washed (1.0 N NaOH then brine), dried(MgSO₄), filtered, and concentrated. Flash chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (2.92 g, 80%). ¹H NMR:consistent with structure.

Preparation 326 (3-Aminomethyl-cyclohexyl)-carbamic acid tert-butylester

[0757] A mixture of a compound from preparation 325 (1 g, 2.76 mmol),10% Pd/C catalyst (0.5 g), and EtOAc (30 mL) was stirred under anatmosphere of hydrogen gas (balloon) for 18 h, filtered through celite,and concentrated to give (0.48 g, 76%) which was taken on withoutfurther purification. Mass Spectrum (ES+) (m/z) 229.1 [M+1].

Preparation 327[3-({[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-methyl)-cyclohexyl]-carbamicacid tert-butyl ester

[0758] To a solution of a compound from preparation 326 (0.48 g, 2.1mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonylchloride (0.75 g, 2.74 mmol) in 1 CH₂Cl₂ (20 mL) under N₂ was addeddropwise Et₃N (0.73 mL, 5.25 mmol) and stirred for 4 h. The reaction wasdiluted with CH₂Cl₂, washed (H₂O then brine), dried (MgSO₄), filtered,and concentrated. Flash chromatography (silica gel, hexanes/EtOAcgradient) gave the title compound (0.726 g, 74%). Mass Spectrum (ES+)(m/z) 366.1 [M−BOC].

Preparation 3285-Chloro-3-(2-chloro-6-fluoro-phenyl)-isoxazole-4-carboxylic acid[3-(benzoylamino-methyl)cyclohexyl]amide

[0759] In a fashion similar to that described for preparation 316, (0.22g, 0.84 mmol), CH₂Cl₂ (2 mL), oxalyl chloride (0.15 mL 1.68 mmol), DMF(0.01 mL), CH₂Cl₂ (5 mL), N-(3-Amino-cyclohexylmethyl)-benzamide (0.15g, 0.65 mmol), and Et₃N (0.35 mL, 2.52 mmol) gave the title compound(0.29 g, 90%) after flash chromatography (silica gel, Acetone/CH₂Cl₂gradient). Mass Spectrum (ES+) (m/z) 490.1 [M+1].

Preparation 3293-(2-Chloro-6-fluoro-phenyl)-5-diethylamino-isoxazolecarboxylic acid{[3-[(2-propenyl-penta-2,4-dienoylamino)methyl]-cyclohexyl}-amide

[0760] To a solution of a compound from preparation 328 (0.1 g, 0.2mmol) in DMF (2.5 mL) under N₂ was added diethylamine (0.065 ml, 0.63mmol) and stirred for 2 h. The reaction was diluted with EtOAc, washed(H₂O then brine), dried (MgSO₄), filtered, and concentrated. (0.1 N HCland brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (silica gel, acetone/CH₂Cl₂ gradient) gave the titlecompound (0.1 g, 93%). Mass Spectrum (ES+) (m/z) 527.2 [M+1].

Preparation 3303-(2-Chloro-6-fluoro-phenyl)-5-pyrrolidin-1-yl-isoxazole-4-carboxylicacid [3-(benzoylaminomethyl)-cyclohexyl]-amide

[0761] In a fashion similar to that described for preparation 329, acompound from preparation 328 (0.085 g, 0.17 mmol), DMF (2.5 mL),pyrrolidine (0.14 mL, 1.7 mmol) gave (0.089 g, 100%) which was taken onas a crude residue. Mass Spectrum (ES+) (m/z) 525.2 [M+1].

Preparation 3313-(2-Chloro-6-fluoro-phenyl)-5-ethylamino-isoxazole-4-carboxylic acid[3-(benzoylaminomethyl)-cyclohexyl]-amide

[0762] In a fashion similar to that described for preparation 329, acompound from preparation 328 (0.085 g, 0.17 mmol), DMF (2.5 mL),ethylamine (0.85 mL 1.7 mmol) gave the title compound (0.085 g, 100%)which was taken on as a crude residue. Mass Spectrum (ES+) (m/z) 499.2[M+1].

Preparation 3323-(2-Chloro-6-fluoro-phenyl)-5-ethylsulfanyl-isoxazole-4-carboxylic acid[3-(benzoylamino-methyl)-cyclohexyl]-amide

[0763] In a fashion similar to that described for preparation 329, acompound from preparation 328 (0.1 g, 0.2 mmol), DMF (2.5 mL), sodiumethanethiolate (0.103 g, 1.0 mmol) gave the title compound (0.85 g,100%) which was taken on as a crude residue. ¹H NMR: consistent withstructure.

Preparation 333[3-({[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-methyl)-cyclohexyl)-carbamicacid tert-butyl ester

[0764] A mixture of a compound from preparation 326 (0.85 g, 2.35 mmol),10% Pd/C catalyst (0.5 g), and EtOAc (25 mL) was stirred under anatmosphere of hydrogen gas (balloon) for 18 h, filtered through celite,and concentrated. This residue was mixed with3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride (0.772g, 2.82 mmol) in CH₂Cl₂ (7 mL) under N₂ and to this solution was addeddropwise Et₃N (1.0 mL, 7.05 mmol). After stirring 48 h, the mixture wasdiluted with CH₂Cl₂, washed (0.1 N HCl then brine), dried (MgSO₄),filtered, and concentrated. Flash chromatography (silica gel,EtOAc/Hexanes gradient) gave the title compound (0.64 g, 58%). MassSpectrum (ES+) (m/z) 366.3 [M−BOC].

Preparation 3345-[3-(Benzoylamino-methyl)-cyclohexyl]-3-methyl-4-oxo-4,5-dihydro-isoxazolo[4,3-c]quinolin-9-yl}-carbamicacid 2-trimethylsilanyl-ethyl ester

[0765] To a solution of3-methyl-4-oxo-5-(3-[(phenylcarbonylamino)methyl]-cyclohexyl]-5-hydroisoxazolo[4,3-c]quinoline-9-carboxylicacid (0.25 g, 0.55 mmol), Et₃N (0.118 mL, 0.845 mmol) in toluene (3.5mL) under N₂ was added DPPA (0.18 mL, 0.845 mmol) and 2-(trimethylsilyl)ethanol (0.232 mL, 1.63 mmol). The solution was heated to reflux for 4h. The reaction was cooled to rt., diluted with EtOAc, washed (1.0 NNaOH then brine), dried (MgSO₄), filtered, and concentrated. Columnchromatography (silica gel, acetone/CH₂Cl₂ gradient) gave the titlecompound (0.285 g, 90%). Mass Spectrum (ES−) (m/z) 573.3 [M−1]

Preparation 335[3-(3,4,5-Trimethoxy-phenylcarbamoyl)-cyclopentylmethyl]-carbamic acidtert-butyl ester

[0766] To a solution of 0.224 g (0.92 mmols) of3-[(t-butoxy)amino]cyclopentane-carboxylic acid was added 0.44 mmol of1-hydroxy-7-azabenzotriazole and 0.44 mmol of EDCI. After 40 minutes,0.44 mmol of 3,4,5-trimethoxyaniline was added. After 3.25 hours, thesolvent was removed in vacuo and replaced with ethyl acetate. Theorganic layer was rinsed with 1 N HCl, aq. NaHCO₃, and then ×3 withwater. The organic layer was dried and the solvent was removed in vacuoto yield 0.34 g of the title compound. MS(ES+)m/z=409.

Preparation 336 3-Aminomethyl-cyclopentanecarboxylic acid(3,4,5-trimethoxy-phenyl)-amide

[0767] A solution of 0.049 g (0.12 mmol) of a compound from preparation335 in TFA (10 ml) was stirred for 1 hour, after which the TFA wasremoved in vacuo and replaced with ethyl acetate. The organic layer wasrinsed with 1N NaOH followed by brine and dried. The organic layer wasremoved in vacuo to yield 0.013 g of the title compound. MS(ES+)m/z=308.

Preparation 337 3-(2-Chloro-6-fluoro-phenyl)₅-methyl-isoxazolecarboxylicacid [3-(3,4,5-trimethoxy-phenylcarbamoyl)cyclopentylmethyl)-amide

[0768] A solution of 0.013 g (0.042 mmol) of a compound from preparation336, 0.03 g (0.46 mmol) of3-(6-chloro-2-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride, and0.07 ml (0.5 mmol) of triethylamine in dichloromethane (10 ml) wasstirred for 12 hours. The solvent was removed in vacuo and replaced withethyl acetate. The organic layer was washed with 1N HCl, then aq.NaHCO₃, followed by brine and dried. The solvent was removed in vacuothen chromatographed on silica gel with CH₂Cl₂ 100% to CH₂Cl₂/MeOH 2% toyield 0.018 g of the title compound. MS(ES+)m/z=545.8.

Preparation 338(3-{[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-cycloheptyl)-aceticacid methyl ester

[0769] A solution of 4.4 g (24 mmol) of methyl2-(3-aminocycloheptyl)acetate, 0.03 g (0.46 mmol) of3-(6-chloro-2-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride, and0.07 ml (0.5 mmol) of triethylamine in dichloromethane (10 ml) wasstirred for 12 hours. The solvent was removed in vacuo and replaced withethyl acetate. The organic layer was washed with 1N HCl, then aq.NaHCO₃, followed by brine and dried. The solvent was removed in vacuothen chromatographed on silica gel with hexane/EtOAc 311 to yield 1.7 gof the title compound. MS(ES+)m/z=423.

Preparation 3395-(3-Aminomethyl-cycloheptyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0770] To a solution of 0.43 g (1.02 mmol) ofN-{[3-(9-chloro-3-methyl-4-oxo(5-hydroisoxazolo[4,3-c]quinolin-5-yl))cycloheptyl]methyl}methoxycarboxamidein CH₂Cl₂ (10 mL) was added 0.35 mL of trimethylsilyl iodide(2.1 mmol)and the solution was stirred for 15 hours at ambient temperature. MeOH(1.5 mL) was added and the reaction was stirred for 15 min. before thesolvent was removed in vacuo. The residue was dissolved in CH₂Cl₂ andrinsed with 1N NaOH followed by 50% brine/water. After drying overNa₂SO₄, the solvent was removed to yield 0.397 g of the title compound.MS(ES+)m/z=360.1.

Preparation 340 tert-butylamino-pyridin-3-yl-acetic acid ethyl ester

[0771] A typical synthesis of bromo-pyridin-3-yl-acetic acid ethyl esteris described: A solution of fresh lithium diisopropylamide (LDA) wasprepared at −10° C. from diisopropylamine (8.54 mL; 60.5 mmol) andn-butyllithium (nBuLi) (37.8 mL of a 1.6 M hexanes solution; 12.1 mmol)and stirred for 10 min. After chilling the fresh LDA to −78° C., ethyl3-pyridylacetate (9.21 mL; 60.5 mmol) was added and the solution wasstirred another 10 min. TMSCl (7.68 mL; 60.5 mmol) was added to theresulting opaque yellow slurry and the solution was stirred 5 min.Finally a solution of 4-(dimethylamino) pyridinium tribromide (22.0 g;60.5 mmol) in tetrahydrofuran was added and the reaction solution wasstirred 10 min. After warming to rt. the reaction solution was quenchedwith saturated NH₄CL (aq) and extracted twice with ethyl acetate. Thecombined organic layer was washed once with saturated NaCl (aq), driedwith Na₂SO₄, filtered, and concentrated in vacuo. The resultingbromo-pyridin-3-yl-acetic acid ethyl ester was an unstable brown oil andwas therefore used immediately by preparing aliquots of product indichloromethane and proceeding.

[0772] Bromo-pyridin-3-yl-acetic acid ethyl ester (2.4 g; 9.8 mmol) wasreacted in refluxing CH₂Cl₂, overnight with tert-butylamine (6.2 mL;55.8 mmol; 6 equiv) and Et₃N (2.8 mL; 19.6 mmol; 2 equiv). The reactionsolution was evaporated to dryness, dissolved in CH₂Cl₂, washed sixtimes with saturated NaHCO₃ (aq), washed once with saturated NaCl (aq),dried with Na₂SO₄, filtered, and concentrated in vacuo. The resultingbrown oil was purified with silica gel chromatography in a 6×8 cm glasscolumn using a 30% EtOAc/hexanes (v/v) mobile phase. A total of 955 mgdesired product was isolated (41% yield). MS(ES) calc'd: [M+H]+=237.1m/z. Found: 237.1 m/z.

Preparation 341 (2,2-dimethyl-propylamino)-pyridin-3-yl-acetic acidethyl ester

[0773] Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol),prepared in a manner similar to preparation 340, was reacted inrefluxing CH₂Cl₂, overnight with neopentylamine (4.83 mL; 41.0 mmol; 4equiv) and Et₃N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution wasevaporated to dryness, dissolved in CH₂Cl₂, washed five times withsaturated NaHCO₃(aq), washed once with saturated NaCl(aq), dried withNa₂SO₄, filtered, and concentrated in vacuo. The resulting brown oil waspurified with silica gel chromatography in a 3×25 cm glass column usinga 0.5% methanol/chloroform (v/v) mobile phase. A second columnpurification with 100% chloroform followed by 1% methanol/chloroform(v/v) produced pure product as a yellow oil (1.0 g; 40% yield). MS(ES)calc'd: [M+H]⁺=250.1 m/z. Found: 250.1 m/z.

Preparation 342 Dimethylamino-pyridin-3-yl-acetic acid ethyl ester

[0774] Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol) wasreacted in a sealed tube, at rt., in CH₂Cl₂, overnight withN,N-dimethylamine hydrochloride (3.34 g; 41.0 mmol; 4 equiv) and Et₃N(5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated todryness, dissolved in CH₂Cl₂, washed five times with saturated NaHCO₃(aq), washed once with saturated NaCl (aq), dried with Na₂SO₄, filtered,and concentrated in vacuo. The resulting brown oil was purified withsilica gel chromatography in a 3×25 cm glass column using a 0.5%methanol/chloroform (v/v) mobile phase. The desired product was isolatedas a yellow oil (1.12 g; 53% yield). MS(ES) calc'd: [M+H]+=208.1 m/z.Found: 208.1 m/z.

Preparation 343 (4-methyl-piperazin-1-yl)-pyridin-3-yl-acetic acid ethylester

[0775] Bromo-pyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol),was reacted in refluxing dichloromethane, overnight with1-methylpiperazine (4.54 mL; 41.0 mmol; 4 equiv) and Et₃N (5.8 mL; 41.0mmol; 4 equiv). The reaction solution was evaporated to dryness,dissolved in CH₂Cl₂, washed five times with saturated NaHCO₃ (aq),washed once with saturated NaCl (aq), dried with Na₂SO₄, filtered, andconcentrated in vacuo. The resulting brown oil was purified with silicagel chromatography in a 3×17 cm glass column using a 2%methanol/chloroform (v/v) mobile phase. A second column eluted with 30%EtOAc/hexanes (v/v) followed by a step gradient of 0.5-3%methanol/CH₂Cl₂ (v/v) produced the desired product as a yellow oil (756mg; 28% yield). MS(ES) calc'd: [M+H]+=263.1 m/z. Found: 263.1 m/z.

Preparation 344 2-{3-[(t-Butoxy)carbonylamino]cyclohexyl}acetic acid

[0776] A compound from preparation 45 (1.0 g, 2.77 mmol) was dissolvedin tetrahydrofuran (4 mL) and ethanol (4 mL) under a dry nitrogenatmosphere at room temperature. This cloudy white solution became clearand colorless after mixing with 2N NaOH_((aq)) (15 mL; 19.4 mmol, 11.1equiv) for 2 h. After rotary evaporation to dryness, the white solid wasdissolved in water (20 mL) and the resulting solution extracted withdiethyl ether (twice). Acidification of the aqueous layer to pH 2 with1N HCl(aq) produced a white solid that was extracted into ethyl acetate(thrice). The EtOAc was washed with saturated NaCl(aq), dried withNa₂SO₄(s), and concentrated to dryness by rotary evaporation. Theresulting white solid (700 mg, 98% yield) was used in subsequentreactions without further purification. MS(ES) calc'd: [M+Na]+=280.2m/z, [M−H]⁻=256.2 m/z. Found: 280.1 m/z; 256.2 m/z.

Preparation 345N-((1S,3R)-3-{[(phenylmethoxy)carbonylamino]methyl}cyclohexyl)(t-butoxy)carboxamide

[0777] To a solution of a compound from preparation 344 (3.43 g, 13.35mmol), Et₃N (3.75 mL, 26.96 mmol) in toluene (86 mL) under N₂ was addedDPPA (5.8 mL, 26.96 mmol) and benzyl alcohol (4.28 mL, 41.38 mmol). Thesolution was heated to reflux overnight. The reaction was cooled to rt.,diluted with EtOAc, washed (1.0N NaOH then brine), dried (MgSO₄),filtered, and concentrated. Column chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (3.05 g, 63%). MassSpectrum (ES+) (m/z) 263.1 [M−BOC].

Preparation 346N-(cis-3(S)-Aminocyclohexylmethyl)(phenylmethoxy)carboxamide

[0778] A compound from preparation 345 (1.0 g, 2.76 mmol) was treatedwith TFA (5 mL) under N2. After 20 min of stirring at rt. the reactionwas complete. The crude was then concentrated to an oil which waspurified on a Varian Bond-Elut SCX column (10 g). The column was elutedconsecutively with CHCl₃, MeOH, and ammonia (2.0M in MeOH). The pureproduct was recovered from the ammonia fractions. The solvent wasremoved in vacuo to afford 0.632 g (87%) as a colorless oil. MS (ES+)m/z 263.0 (M+H]⁺.

Preparation 347(3-{[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazolecarbonyl]-aminb}-cyclohexylmethyl)-carbamicacid benzyl ester

[0779] To a mechanically stirred solution of crude compound frompreparation 346 (20.1 g, 76.6 mmol) and TEA (46.9 g, 459.4 mmol) in 185ml of dichloromethane was added a compound from preparation 344 (23.1 g,84.2 mmol) in one portion. The solution warmed slightly and aprecipitate began to form. The reaction mixture was stirred at ambienttemperature for 19 hours. TLC analysis (20% EtOAc/dichloromethane)showed complete consumption of the starting material. The reactionmixture was diluted with 200 ml of dichloromethane and washedsequentially with 2×200 ml of 1N hydrochloric acid, 2×200 ml ofsaturated aqueous sodium bicarbonate solution, and 200 ml ofhalf-saturated aqueous NaCl solution. The solution was dried overmagnesium sulfate and concentrated to a pale yellow oil, whichsolidified upon standing. The solid was triturated with 150 ml ofdiethyl ether, stirred for one hour, filtered, washed with a smallamount of diethyl ether, and dried in vacuo at 25° C. to provide 29.3 g(76%) of the title compound as a white solid. ¹H NMR (300 MHz, CDCl₃)7.48 (m, 1H), 7.35 (m, 6H), 7.17 (dt, J=8.5 Hz, 0.9 Hz, 1H), 5.08 (s,2H), 4.98 (d, J=7.9 Hz, 1H), 4.72 (m, 1H), 3.73 (m, 1H), 3.01 (m, 2H),2.76 (s, 3H), 1.90 (m, 1H), 1.67 (m, 3H), 1.52 (m, 1H), 1.28 (m, 1H),0.69 (m, 2H), 0.43 (q, J=12.0 Hz, 1H).

Preparation 348[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-carbamicacid benzyl ester

[0780] To a mechanically stirred solution of compound from preparation347 (27.6 g, 55.2 mmol) in 450 ml of DMP was added a 0.5M solution ofpotassium bis(trimethyl-silyl)amide in toluene (133 ml, 66.3 mmol) over15 minutes. The resulting purple solution was stirred at ambienttemperature for 5 minutes at which time TLC analysis (20%EtOAc/dichloromethane) indicated that all of the starting material hadbeen consumed. The reaction was diluted with 1 L of EtOAc and quenchedwith 500 ml of water. The two layers were stirred together for 15minutes and separated. The aqueous layer was extracted twice with 250 mlof EtOAc and the combined organic layers were washed twice with 500 mlof water and once with 500 ml of half-saturated NaCl solution. Thesolution was dried over magnesium sulfate and concentrated to an orangesolid. The solid was slurried in a minimal amount of EtOAc, filtered,washed with a small amount of ethyl acetate, and dried in vacuo toafford 17.9 g of the title compound as an off-white solid. An additional4.4 grams of the title compound were isolated by flash chromatography ofthe filtrate. Total yield was 22.3 g (84%). ¹H NMR (300 MD, 1 CDCl₃)7.40 (m, 2H), 7.33 (m, 61), 5.06 (s, 2H), 4.85 (m, 1H), 3.16 (m, 2H),2.89 (s, 3H), 2.56 (br m, 1H), 2.37 (br m, 1H), 1.98 (m, 1H), 1.81 (m,5H), 1.46 (m, 1H), 1.07 (m, 1H).

Preparation 3495-(3-Aminomethyl-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydroiodide

[0781] To a 0° C. solution of compound from preparation 348 (5.0 g, 10.4mmol) in dichloromethane (100 mL) was added iodotrimethylsilane (3.6 mL,25.0 mmol) dropwise, and the solution allowed to warm to roomtemperature overnight. Methanol (6.1 mL, 150.0 mmol) was added dropwiseover two minutes, and the reaction stirred for 30 minutes. The reactionwas concentrated and suspended in ethyl ether. After 15 minutes ofsonication, the solids were removed by filtration and washed with ethylether. The tan powder was dried on a vacuum pump to give 4.61 g of thetitle compound as the 1.2 HI salt, 89% yield. MS (ion spray) 346 (M⁺).

Preparation 350 (t-Butoxy)-N-[(3-nitrophenyl)methyl]carboxamide

[0782] To a suspension of 5.00 g (26.5 mmol) of 3-nitrobenzylaminehydrochloride in 100 mL CH₂Cl₂ at rt. was added 5.79 g (26.5 mmol) ofdi-t-butyl dicarbonate. To this was added 8.13 mL (58.3 mmol) oftriethylamine, dropwise over 15 min. The reaction was stirred for 3 h atrt., after which it was diluted with 300 mL of EtOAc. The resultingorganic solution was washed three times with 1N HCl solution, dried oversodium sulfate and concentrated in vacuo to give 6.2 g (93%) of a whitesolid, which was characterized as the title compound. MS (FIA) m/z=253.

Preparation 351 (t-Butoxy)-N-[(3-aminocyclohexyl)methyl]carboxamide

[0783] To a solution containing 12.0 g (47.7 mmol) of a compound frompreparation 350 in 300 mL ethanol was added 6.0 g of rhodium on carbon.The reaction was subjected to hydrogenation (60 psi) at 60° C. for 18 h,after with the catalyst was removed by vacuum filtration and the solventremoved in vacuo, giving 9.5 g (87%) of a clear oil. This material wascharacterized as the title compound and used without furtherpurification. ¹H-NMR is consistent with structure.

Preparation 352N-(3{[t-Butoxy)carbonylamino]methyl}cyclohexyl)-[4-(2-chloro-6-fluorophenyl)-2-methyl(3-furyl)]carboxamide

[0784] To a solution of 9.5 g (41.6 mmol) of a compound from preparation351 in 200 mL of CH₂Cl₂ was added 11.4 g (41.6 mmol) of a compound frompreparation 344, followed by 11.6 mL (83.2 mmol) of TEA at rt. Thereaction was stirred at room temperature for 15 h, and concentrated invacuo. The crude solid was dissolved in 200 mL of ethyl acetate and theorganic solution was washed twice with 1N HCl solution, dried oversodium sulfate and concentrated in vacuo to give a yellow solid. Thismaterial was recrystallized from methanol to give 12.5 g (64%) of awhite crystalline solid, which was characterized as the title compound,as an inseparable mixture of cis and trans isomers. MS(FIA) m/z=466.2.

Preparation 353(t-Butoxy)-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}carboxamide

[0785] To a stirred solution of 7.00 g (15.0 mmol) of a compound frompreparation 352 in 200 mL of DMF at rt. was added 30.0 mL (15 mmol) of a0.5 M toluene solution of potassium bis(trimethylsilyl) amide over 10min. The resulting dark red reaction was stirred an additional 5 min atrt. and added to 200 mL of 1N HCl. The two phase solution was dilutedwith 400 mL of ethyl acetate and the organic layer was separated. Theorganic solution was washed four times with brine, dried over sodiumsulfate and concentrated in vacuo to give an orange solid. This materialwas recrystallized from toluene to give 3.4 g of a light yellow solid,which was characterized as pure racemic cis material, (a). MS(FIA)m/z=446.1. Purification of the racemic trans material (b) wasaccomplished by concentrating the mother liquor and subjecting thismaterial to flash chromatography on silica gel, using 50% hexane-EtOAcas the eluent. The major fractions were combined to give a light yellowsolid, which was characterized as pure racemic trans material. MS(FIA)m/z=446.1.

Preparation 354

[0786]N-{3-(9-chloro-3-methyltoxo-SH-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methy}(t-butoxy)carboxamide

[0787] The racemic material of a compound from preparation 353 wasseparated into its enantiomers by chiral HPLC chromatography using aChiralpak AD column and 10% ethyl alcohol-heptane as the eluent at aflow of 1.0 mL/min.

[0788] Retention Time (Enantiomer 1)=10.501 min.

[0789] Retention Time (Enantiomer 2)=12.576 min.

Preparation 355N-[3-(aminomethyl)cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0790] A slurry of a compound from 354 (1.2 g, 2.7 mmol) in 20 mL ofacetic acid saturated with hydrochloric acid was stirred for 4 h at rt.,then concentrated to dryness. The residue was dissolved in toluene andconcentrated to dryness. The residue was t slurried in ether/hexanes,concentrated to dryness, and dried under vacuum to yield 750 mg (80%) ofthe desired mixture of isomers as a tan solid. MS (ion spray) 346.2(M+1).

Preparation 357 1-Methyl-piperidine-3-carboxylic acid

[0791] To a solution of ethyl 1-methylnipecotate, 0.3 mL (1.65 mmol) in10 mL of dioxane was added a solution of 118 mg (4.95 mmol) of lithiumhydroxide in 10 mL of water. The solution was stirred for 1.5 hours atrt. then was acidified to pH=1 with 5N HCl. The mixture was concentratedto dryness and carried on without further purification. IS (MS) 144.1(M+1).

Preparation 358 Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester

[0792] To a solution of nipecotic acid, 2.0 g (16.0 mmol) in 20 mL ofTHF and 20 mL of water was added 4.7 g (33.6 mmol) of potassiumcarbonate and 3.5 g (16.0 mmol) of Boc-anhydride. The resulting solutionwas stirred overnight at ambient temperature then concentrated todryness. The residue was dissolved in water, washed with ether andacidified to pH=2 with 5N HCl. The acidic aqueous layer was extractedwith 20% isopropanol/chloroform. The combined organics were washed withbrine, dried over sodium sulfate, filtered and concentrated to drynessto yield 3.2 g (86%) of the desired mixture of isomers as a white solid.MS (ion spray) 228.2 (M−1).

Preparation 359{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-methyl}-carbamicacid tert-butyl ester

[0793] To a solution of a compound from preparation 69, 130 mg (0.28mmol) in 10 mL of DMF was added 59 mg (0.34 mmol) ofN-t-butoxycarbonylglycine, 46 mg (0.34 mmol) of1-hydroxy-7-azabenzo-triazole, 66 mg (0.34 mmol) of EDC, 5 mg of DMAPand 0.120 mL (0.84 mmol) of Et₃N. The reaction mixture was stirredovernight at rt. and was concentrated to dryness. The residue wasdissolved in 20% isopropanol/chloroform, washed with saturated NaHCO₃,washed with brine, dried over Na₂SO₄, filtered and concentrated todryness. The residue was purified by radial chromatography using aMeOH/chloroform gradient and concentrated to dryness. The residue wasslurried in ether/hexanes and concentrated to dryness to yield 97 mg(71%) of the desired isomer as a white foam. MS (ion spray) 489.1 (M+).

Preparation 3602-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamidehydrochloride

[0794] A solution of the compound from preparation 359,49 mg (0.10 mmol)in 10 mL of HCl-saturated acetic acid was stirred 3 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredisomer as a tan foam. MS (ion spray) 389.1 (M+).

Preparation 361 2-(Pyridin-3-yloxy)-hexanoic acid ethyl ester

[0795] To a solution of ethyl-3-bromohexanoate, 5.0 g (22.4 mmol) in 200mL of tetrahydrofuran was added 4.6 g (26.9 mmol) of 3-hydroxypyridinesodium salt The mixture was refluxed for four hours and concentrated todryness. The residue was partitioned between 20% isopropanol/chloroformand water. The organics were washed with saturated aqueous sodiumbicarbonate, washed with brine, dried over sodium sulfate, filtered, andconcentrated to dryness. The residue was purified by columnchromatography using a methanol/chloroform gradient as eluent andconcentrated to dryness to yield 1.82 g (34%) of the desired mixture ofisomers as a brown liquid. MS (ion spray) 238.2 (M+1).

Preparation 362 2-(Pyridin-3-yloxy)-hexanoic acid

[0796] A solution of lithium hydroxide, 200 mg (8.82 mmol) in 10 mL ofwater was added to a solution of compound from the preparation 361, 700mg (2.94 mmol) in 10 mL of dioxane. The resulting solution was stirredat ambient temperature for 3 hours, acidified to pH=1 with 5 N HCl andconcentrated to dryness. Crude MS (ion spray) 210.0 (M+1) for desiredmix of isomers. Crude product was carried on as is without furtherpurification.

Preparation 363 (Pyrimidin-2-yloxy)-acetic acid ethyl ester

[0797] To a slurry of sodium hydride (60% dispersion in mineral oil),280 mg (5.76 mmol) in 10 mL of DMF at 0° C. was added 0.52 mL (4.8 mmol)of ethyl glycolate. After 10 minutes, 0.92 g (5.76 mmol) of2-bromopyrimidine was added. The reaction mixture was stirred 15 min at0° C. then ice bath was removed. After four hours, reaction mixture wasquenched with methanol and concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and water, then extractedwith 20% isopropanol/chloroform. The combined organics were washed withsaturated aqueous sodium bicarbonate, washed with brine, dried oversodium sulfate, filtered, and concentrated to dryness. The residue waspurified by radial chromatography using a methanol/chloroform gradientas eluent and concentrated to dryness to yield 0.45 g (52%) of thedesired product as a colorless oil. MS (ion spray) 183.1 (M+1).

Preparation 364 (Pyrimidin-2-yloxy)-acetic acid

[0798] A solution of lithium hydroxide, 260 mg (11.0 mmol) in 5 mL ofwater was added to a solution of 400 mg (2.2 mmol) of compound frompreparation 363 in 5 mL of dioxane. The mixture was stirred for fourhours at ambient temperature, then was acidified to pH=1 with 5 N HCland concentrated to dryness. The residue was carried on without furtherpurification. MS (ion spray) 155.1 (M+1).

Preparation 3653-Methyl-5-(2-chloro-6-fluorophenyl)₄-isoxazolecarboxylic acid ethylester

[0799] To a solution of ethyl 3-aminomethyl crotonate. (4.79 g, 33.5mmol) in toluene (10 mL), was added triethylamine (3.73 g, 37 mmol). Thesolution was chilled using an ice bath, and then2-chloro-6-fluorobenzoyl chloride (6.47 g, 33.5 mmol) was added dropwiseover a 20 min period. The reaction was allowed to warm slowly to r.t.,and stirred for 24 hr. The resulting suspension was then filtered, andthe filtrate diluted with ethyl acetate (100 mL) and transferred to aseparatory funnel. The organic layer was sequentially washed with water,brine, dried (sodium sulfate), and the volatiles removed under reducedpressure to provide2-(2-chloro-6-fluorobenzoyl)-3-methylamino-but-2-enoic acid ethyl ester(9.46 g) as a golden solid, and primarily one geometrical isomer. MS(ES) m/z 299.9 (M+H)⁺.

[0800] Crude adduct was then redissolved in glacial HOAc (50 mL) towhich was added NH₂OH.HCl (1.8 g, 1.1 eq). The solution was then heatedto reflux for 40-45 min to effect isoxazole formation. The reactionmixture was concentrated to an oil, diluted with ether, and transferredto a sep. funnel. The organic phase was washed with saturatedbicarbonate, brine, then dried. Filtration and concentration affordedcrude isoxazole ethyl ester (7.5 g), which could be used without furtherpurification. MS (+ES) m/z 283.9

Preparation 366 4-Isoxazolecarboxylic acid, 3-Methyl,5-(2-chloro-6-fluorophenyl)

[0801] Hydrolysis of a compound from preparation 365 was accomplished bydissolving the crude ester (7.5 g, approx. 0.027 mol) in THF (250 mL),and adding aq. LiOH (1.344 g in 100 mL, 2 eq). After stirring overnightat r.t., the solution was concentrated to ⅔^(rd) volume, diluted withEtOAc (200 mL) and 50 mL water, transferred to a separatory funnel, andthe aqueous phase collected. The organic phase was washed twice, and thecombined aqueous phase was then acidified with 5N HCl. Back extractionwith three washings of EtOAc was then followed with a brine wash of thecombined organics. After drying over Na₂SO₄, filtration andconcentration, clean isoxazole acid was obtained (2.94 g). MS (−ES) m/z253.8, 255.8 (M−H)⁻.

Preparation 3675-(2-Chloro-6-fluoro-phenyl)-3-methyl-isoxazole-4-carbonyl chloride

[0802] To a solution of a compound from preparation 366 (60 mg, 0.234mmol) in benzene (4 mL) containing catalytic amount of pyridine (20 μl)was added oxalyl chloride (23 mL). After heating to reflux for 1 hr, analiquot was concentrated under vacuum. 1H-NMR (CDCl₃) 7.53 (d of t, 1H),7.37 (d, 1H), 7.17 (t, 1H). (racemic)

Preparation 368 1,3-cyclohexanedicarboxylic acid

[0803] To a suspension of isophthalic acid (500 g, 3 mol) in methanol(2.8 l) was added 5% Rhodium-on-alumina catalyst (50 g) and acetic acid(150 ml). The reaction mixture was shaken under hydrogen (50 psi) atroom temperature overnight. The mixture was filtered through celite. Tothis solution was added fresh 5% Rhodium-on-alumina catalyst (25 g), andthe mixture was shaken under 50 psi of hydrogen for another 24 hours.The final reaction mixture was filtered through celite. The solution wasconcentrated under vacuum to give 493 g of the title compound as a whitepowder (96.3% yield). m.p. 163-165° C.

Preparation 369 3-Oxabicyclo[3.3.1]nonane-2,4-dione

[0804] A solution of dicyclohexylcarbodiimide (200 g, 1.16 mol) inCH₂Cl₂ (1000 ml) was added dropwise to a suspension of compound frompreparation 368 (257 g, 1.25 mol) in CH₂Cl₂ (550 ml), and the mixturewas stirred at room temperature for 4 hours. The precipitateddicyclohexylurea was filtered and washed several times with cold CH₂Cl₂(200 ml×3). The combined organic layer was concentrated to give a whitesolid, which was suspended in MTBE (900 ml). This solid was collected byfiltration, washed with MTBE (250 ml), and dried under house vacuum togive the title compound (137 g). The filtrate was concentrated to aresidue, which was suspended in MTBE (250 ml) to give another 31 ganhydride. The total yield was 168 g (94%). m.p. 138-140° C.

Preparation 370 cis-1,3-Cyclohexanedicarboxylic acid diethyl ester

[0805] To a solution of compound from preparation 369 (31 g, 0.2 mol) inethanol (anhydrous, 310 ml) was added p-toluenesulfonic acid monohydrate(1.9 g, 10 mmol, 0.05 equiv.) and triethyl orthoformate (50 ml, 0.3mol). The reaction mixture was stirred at 60° C. overnight. Thevolatiles were stripped and the residue was diluted with ethyl acetate(250 ml), washed with water (120 ml) and brine (100 ml), and dried overMgSO₄. After filtration and evaporation, the residue was purified bychromatography. Eluting the column with 10% ethyl acetate in hexaneafforded the title compound (40 g, 87.7% yield). ¹H NMR: (500 MHz,CDCl₃) δ 4.11 (q, J=7.0 Hz, 4H), 2.29 (dt, 2H), 2.11 (dd, 1H), 1.97 (m,2H), 1.98 (m, 1H), 1.53 (q, J=12.5 Hz, 2H), 1.30-1.40 (m, 2H), 1.25 (t,J=7.0 Hz, 6H).

Preparation 371 1,3-Cyclohexanedicarboxylic acid, monoethyl ester(1R,3S)

[0806] To a suspension of compound from preparation 370 (40 g, 17.5mmol) in pH 7.2 phosphate buffer [0.2 M] (1.2 l) was added lipase AY30(Amano, 16.7 g). The mixture was stirred vigorously at room temperaturefor 30 hours. The mixture was acidified with 10-15% HCl to pH<2, andextracted with ethyl acetate (500 ml×2). The combined organic solutionwas washed with aqueous 10% Na₂CO₃ (100 ml×2) and water (100 ml×2). Thecombined aqueous layers were washed again with ethyl acetate (150 ml)and then acidified with 10-15% HCl to pH<2. The acidified aqueous wasthen extracted with ethyl acetate (150 ml×3). The combined organicsolution was dried over MgSO₄. After filtration and concentration thetitle compound (35.6 g, 100% yield) was obtained. ¹H NMR (500 MHz,CDCl₃) a 4.12 (q, J=7.0 Hz, 2H), 2.20-2.40 (m, 3H), 1.85-2.05 (m, 3H),1.5 (q, 2H), 1.35 (m, 2H), 1.24 (t, J=7.0 Hz, 3H), [a]D+3.2°,[α]₃₆₅+10.4 0 (c, 0.434; CHCl₃). [a]D+3.0°, [a]365+9.6° (c, 0.532;CH₃OH).

Preparation 372 Ethyl-[3-N-(methylcarbamate)-cyclohexyl]-carboxylate(1R,3S)

[0807] A solution of a compound from preparation 371 (73 g, 365 mmol) intoluene (750 ml) was heated to reflux using a Dean-Stark trap toseparate trace amounts of water. After collecting about 10 ml of water,the mixture was cooled down to about 40-50° C. To this mixture was addedtriethylamine (56 ml, 0.4 mol), and diphenylphosphoryl azide (86.5 ml,0.4 mol). The reaction mixture was stirred at 110° C. for 60 min, cooledto 70° C., and methanol (64 g, 2 mol) was added with stirring. Afteraddition, the final reaction mixture was then heated to 85° C.overnight. After cooling to room temperature, the mixture was dilutedwith ethyl acetate (700 ml) and washed with water (500 ml). The aqueouslayer was extracted with ethyl acetate (500 ml×2). The combined organicsolution was washed again with water (500 ml) and brine (500 ml). Afterdrying over MgSO₄ and concentration under reduced pressure, the titlecompound was obtained as a colorless oil (86 g, 100%). ¹H NMR: (300 MHz,CDCl₃) δ 4.60 (sb, 1H), 4.13 (q, 2H), 3.65 (s, 3H), 3.50 (sb, 1H), 2.38(t, 1H), 2.23 (d, 1H), 2.00-1.80 (m, 3H), 1.24 (t, 3H), 1.12-0.95 (m,1H).

Preparation 373Ethyl-((1R,3S3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl-amino}cyclohexyl)-carboxylate

[0808] To a solution of compound from preparation 372 (86 g, 365 mmol)in CH₂Cl₂ (750 ml) was added iodotrimethylsilane (100 g, 500 mmol) inone portion, at room temperature. The reaction mixture was stirred for 2hours at ambient temperature, cooled to 0-5° C., and methanol (50 ml)was added. After stirring 15 minutes, the solution was concentratedunder reduced pressure. The residue was dissolved in THF (1 l). To thissolution was added water (0.5 l), potassium carbonate (138 g, 1 mol),and a solution of a compound from preparation 27 (110 g, 0.4 mol) in 250ml THF, dropwise. After the addition, the reaction mixture was heated toroom temperature and stirred for 12 hours. THF was removed under housevacuum, water (250 ml) was added, and the mixture was extracted withethyl acetate (500 ml×3). The combined organic solution was washed withsaturated sodium thiosulfate (150 ml), water (500 ml), brine (500 ml)and then dried over MgSO₄. After filtration and evaporation undervacuum, the residue was purified by recrystallization from MTBE (250ml). Repeating this recrystallization procedure three times provided thetitle compound (122.7 g, 82.5% yield) as a white powder. M.S. m/z 409(M⁺, 100%).

Preparation 374 Ethyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quindin-5-yl)-cyclohexyl]-carboxylate

[0809] To a solution of compound from preparation 373 (78 g, 190 mmol)in DMF (750 ml) was added a solution of KHMDS ([0.5M], 400 ml, 200mmol). The temperature was kept at 25° C. by using an ice-bath. Afterthe addition was complete, the reaction mixture was analyzed by TLC(silica gel, 50% EtOAc in hexane) and found to be complete. Water (1 l)was added and the mixture was extracted with EtOAc (800 ml×3). Thecombined organic solution was washed with 1N HCl (250 ml), water (250ml), brine (250 ml), dried over MgSO₄ and concentrated to give a residuewhich was purified by recrystallization from MTBE (500 ml) to afford 66g of the title compound as a light yellow powder (89.0% yield). M.S. m/z389 (M⁺+1, 100%).

Preparation 375 (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarboxylic acid

[0810] To a solution of compound from preparation 374 (62 g, 160 mmol)in THF (600 ml) was added 5N aqueous sodium hydroxide (120 ml) at roomtemperature. The reaction mixture was heated to 60° C. for 15 hours withstirring. After cooling to room temperature, water (750 ml) was addedand the mixture was washed with ethyl acetate (500 ml). The aqueousphase was separated and acidified with 15% HCl to pH<2. The aqueousphase was then extracted with methylene chloride (1000 ml×3). Thecombined organic extracts were washed again with water (500 ml), brine(500 ml), and dried over MgSO₄. After filtration and evaporation undervacuum, the dark brown residue was suspended in MTBE (1000 ml), andrefrigerated overnight. The mixture was filtered to afford. 55.45 g(96.4%) of bright yellow product. M.S. m/e 361 (M+, 50%), 225 (100%).

Preparation 376 2-methyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]carbamate

[0811] To a suspension of compound from preparation 375 (55.4 g, 154mmol) in toluene (1 l) was added triethylamine (23.7 ml, 170 mmo]), anddiphenylphosphoryl azide (36.5 ml, 170 mmol). The reaction mixture wasstirred at 110° C. for 2 hours during which time a solution formed. Thesolution was cooled to 80° C. and methanol (25 g, 0.77 mol) was addedwith stirring. The solution was warmed to 85° C. for 22 hours. Aftercooling to room temperature, the toluene was removed under reducedpressure and the residue was dissolved in dichloromethane (3 l) andwashed with water (1 l). The aqueous phase was extracted withdichloromethane (1 l×2) and the combined organic solution was washedagain with water (500 ml) and brine (500 ml). After drying over MgSO₄,the solution was concentrated under vacuum. The crude product waspurified by crystallization (CH₂C₂/MTBE, 0.5 ½ l) to afford the titlecompound (46.6 g, 78.2%). [α]_(D)+49.2°, [α]₃₆₅+263.3° (c, 0.56; CHCl₃).The filtrate was concentrated to a residue, which was purified bychromatography to obtain a second crop of product (5.1 g). The totalyield was 86.8%. M.S. m/z 476 (M⁺, 25%).

Preparation 377[3-(3-Acetylamino-5-chloro-2-oxo-2H-quinolin-1-yl)-cyclohexyl]-carbamicacid methyl ester

[0812] A compound from preparation 376 (0.1 g, 0.26 mmol) and Mo(CO)₆(0.13 g, 0.51 mmol) were combined in a solution of acetonitrile (5 mL)and water (1 mL). The reaction mixture was heated to reflux whilestirring. After stirring for 2 hr the reaction was complete. A 10%aqueous EDTA solution was added and stirred for an additional 30minutes. The reaction was then transferred to a separatory funnel andwashed with water (5×10 mL). The organic solution was filtered throughcelite and concentrated to a dark brown solid under vacuum. The solidwas diluted in EtOAc and was purified by silica gel columnchromatography using 50% EtOAc in Hexanes to elute the product Thesolvent was removed in vacuo to afford 0.078 g of desired product as awhite solid. MS (ES+) m/z 392.2 (M+H)⁺, (ES−) 390.2 (M−H)⁻.

Preparation 378[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexyl]-carbamicacid methyl ester

[0813] A solution of a compound from preparation 377 (0.05 g, 0.13 mmol)in acetic acid (5 mL) was treated with hydroxylamine hydrochloride (13mg, 0.19 mmol). The solution was heated to reflux and stirred 5 hr. Thereaction was then diluted in EtOAc (50 mL) and washed with water (3×10mL), sat'd sodium bicarbonate (3×10 mL), and brine (2×10 mL). Theorganic was dried over sodium sulfate and the solvent removed The crudeproduct was purified by silica gel column chromatography using 50% EtOAcin Hexanes to elute the product. The solvent was removed in vacuo toafford 0.028 g (56%) of title compound as a white solid. MS (ES+) m/z390.1 (M+H)⁺, (ES−) 388.2 (M−H)⁻.

Preparation 3805-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

[0814] A solution of a compound from preparation 378 (0.38 g, 1.0 mmol)in CH₂Cl₂ (25 mL) was treated with TMSI (0.29 g, 1.5 mmol). The solutionwas stirred for 2 hr at room temperature. The solution was thenconcentrated to a solid and the solid was diluted in EtOAc (100 mL). Theorganic solution was washed with 1.0 N HCl (5×20 mL) and the aqueous wasadjusted to pH-12 with 5.0 N NaOH. The aqueous was then extracted withCH₂Cl₂ and the solvent was removed to afford 0.26 g (80%) of the titlecompound as a white solid. MS (ES+) m/z 332.1 (M+H)⁺.

Preparation 3909-Chloro-3-methyl-5-(3-methylaminomethyl-cyclohexyl)-5H-isoxazolo[4,3-c]quinolin-4-one

[0815] To a solution of a compound from the preparation 48 (50 mg, 0.12mmol) in chloroform (0.6 mL) was added trifluoroacetic acid (0.6 mL) andtriethylsilane (57 μL 0.35 mmol) dropwise. The solution was stirred atrt. under nitrogen overnight. The solution was concentrated anddissolved in chloroform (1 mL) and aqueous 1N HCl solution (1 mL). Tothis mixture was added dichloromethane (10 mL) and saturated sodiumbicarbonate solution (10 mL). The layers were separated, and the aqueouslayer was extracted with dichloromethane (×3). The combined organiclayers were dried over magnesium sulfate and concentrated to give 13.7mg of the title compound as a brown solid, 32% yield. ¹H NMR: consistentwith structure. MS (ion spray) 360 (M⁺).

Preparation 391 Hydroxy-pyridin-2-yl-acetic acid methyl ester

[0816] To a dry flask was added 2-pyridine-carboxaldehyde (14.4 mL, 150mmol) and zinc iodide (5 mg, 0.02 mmol), followed by dropwise additionof trimethylsilyl cyanide (20.7 mL, 152 mmol) with rapid stirring. Thesolution was stirred under nitrogen at rt. overnight. The solution wastreated with 9N HCl (50 mL, aqueous solution), and stirred undernitrogen at reflux overnight. The solution was partitioned between waterand 20% isopropanol/chloroform, and the aqueous layer concentrated to anorange solid. Methanol was added, the mixture was sonicated, and placedin a 0° C.-freezer overnight. Ammonium chloride was removed byfiltration (×2), and the solution concentrated. The solution was dilutedwith water (500 mL), and basified to pH 8 with aqueous 5N NaOH. Theaqueous layer was extracted with 20% isopropanol/chloroform (×3), andthe organic layers were washed with brine, dried over magnesium sulfateand concentrated to give 14.02 g of yellow solid. The material wassonicated as a suspension in diethyl ether and filtered to removebaseline impurities. Purification by silica gel chromatography (elutingwith 0-1% methanol/chloroform) gave 4.10 g of the title compound as ayellow solid, 16% yield. ¹H NMR: consistent with structure. MS (ionspray) 167 (M+).

Preparation 392 (tert-Butyldiethyl-silanyloxy)-pyridin-2-yl-acetic acidmethyl ester

[0817] To a solution of a compound from preparation 391 (4.10 g, 24.5mmol) in DMP (35 mL) was added imidazole (3.34 g, 49.0 mmol) andt-butyldimethylsilyl chloride (7.39 g, 49.0 mmol). The reaction wasstirred at rt. overnight under nitrogen. The reaction was concentratedand dissolved in chloroform, washed with saturated aqueous sodiumbicarbonate solution, brine, dried over magnesium sulfate andconcentrated Purification by flash chromatography on silica gel (elutingwith 10-20% ethyl acetate/hexane) gave 6.07 g of the title compound as aclear oil, 88% yield. ¹H NMR: consistent with structure. MS (ion spray)281 (M⁺).

Preparation 393 Hydroxy-pyridin-3-yl-acetic acid methyl ester

[0818] To a dry flask in an ice bath was added 3-pyridine-carboxaldehyde(14.5 mL, 150 mmol) and zinc iodide (5 mg, 0.02 mmol), followed bydropwise addition of trimethylsilyl cyanide (20.7 ml, 152 mmol). Thesolution was stirred under nitrogen at rt. overnight. The solution wastreated with 9N HCl (50 mL, in water), and stirred under nitrogen atreflux overnight. The solution was partitioned between an aqueous 1N HClsolution and chloroform, and the aqueous layer concentrated. Ethanol wasadded, the mixture was heated to 45° C., and ammonium chloride wasremoved by filtration, and the solution concentrated. To a 0° C. flaskwas added methanol (300 mL) followed by dropwise addition of thionylchloride (40 ml, 548 mmol). After ten minutes, the concentrated reactionmixture was added dropwise as a solution in methanol (300 mL), and thereaction was allowed to warm to rt. overnight. The solution wasconcentrated, diluted with water (500 mL), and basified to pH 9 with asaturated aqueous sodium bicarbonate solution. The aqueous solution wasextracted with 20% isopropanol/chloroform (×5), and the organics driedover magnesium sulfate and concentrated to give 18 g of red oil.Purification by silica gel chromatography (eluting with 0-2%methanol/chloroform) gave 11.51 g of the title compound a yellow oil,46% yield. ¹H NMR: consistent with structure. MS (ion spray) 167 (M⁺).

Preparation 394 1-tert-Butoxycarbonylamino-cyclopentanecarboxylic acid

[0819] To a suspension of 1-amino-1-cyclopentane carboxylic acid (4.52g, 35.0 mmol) in THF (50 mL) and water (50 mL) was added potassiumcarbonate (14.51 g, 105.0 mmol), di-t-butyl-dicarbonate (7.72 g, 35.4mmol), and DMAP (5 mg, 0.04 mmol). The reaction was stirred at rt. undernitrogen overnight. The THF was removed in vacuo, and the remainingaqueous solution was acidified to pH 5.5 with an aqueous 5N HClsolution. The aqueous solution was extracted with 20%isopropanol/chloroform (×6), dried over magnesium sulfate, andconcentrated to give 1.01 g of the title compound as a white solid, 13%yield. ¹H NMR: consistent with structure. MS (ion spray) 229 (M⁺).

Preparation 395 (4-Acetyl-piperazin-1-yl)pyridin-3-yl-acetic acid ethylester

[0820] N-acetyl-piperazine (3.7 g; 28.8 mmol; 2.8 equiv) was combinedwith bromo-pyridin-3-yl-acetic acid ethyl ester (approx. 2.5 g; 10mmol). Purification on a 3×16 cm silica column using a 30% then 40%ethyl acetate/hexanes (v/v) mobile phase followed by a 2%methanol/dichloromethane (v/v) mobile phase resulted in 1.84 g lightyellow oil (approx. 60% yield). MS(ES) calc'd: [M+H]⁺=292.2 m/z;[M+Na]⁺=314.2 m/z. Found: 292.1 m/z; 314.1 m/z.

Preparation 396 Pyridin-3-yl-(pyridin-2-yloxy)-acetic acid ethyl ester

[0821] Sodium hydride (520 mg; 21.8 mmol; 1.4 equiv) was stirred with2-hydroxypyridine (1.73 g; 18.2 mmol; 1.2 equiv) in DMF (30 mL) for 15min. This solution was added to an aliquot of bromo-pyridin-3-yl-aceticacid ethyl ester (approx. 3.6 g; 15 mmol) in DMF (20 mL). After stirringovernight, at rt., the resulting opaque black solution was concentratedin vacuo, dissolved in 20% isopropyl alcohol/chloroform, washed 5 timeswith saturated NaHCO_(3(aq)), washed twice with saturated NaCl_((aq)),and dried over Na₂SO_(4(s)). After filtration, the solution wasconcentrated in vacuo and purified by SiO₂ column chromatography on twoconsecutive columns with a 1% methanol/chloroform mobile phase and thenan ethyl acetate/hexanes mobile phase (30%, 40%, 50% step gradient). Alight yellow oil (134 mg; approx. 3% yield) was isolated. MS(ES) calc'd:[M+H]⁺=259.2 m/z. Found: 259.1 m/z.

Preparation 397 Pyridin-3-yl-(pyridin-3-yloxy)acetic acid ethyl ester

[0822] The product was prepared in a manner similar to preparation 396using the pre-formed sodium salt of the 3-hydroxypyridine (2.13 g; 18.2mmol; 1.2 equiv) and an aliquot of bromo-pyridin-3-yl-acetic acid ethylester (approx. 3.6 g; 15 mmol) in dimethylformamide (20 mL). Columnpurification over SiO₂ (0.5% then 1.5% methanol/chloroform) produced ayellow/orange oil (2.02; approx. 50% yield). MS(ES) calc'd: [M+H]⁺=259.2m/z; [M−H]⁻=257.2 m/z. Found: 259.1 m/z; 257.1 m/z.

Preparation 398 Pyridin-3-yl-(pyridin-4-yloxy)-acetic acid ethyl ester

[0823] The product was formed in a manner similar to preparation 396using the in situ-generated sodium salt of the 4-hydroxypyridine (2.13g; 18.2 mmol; 1.2 equiv) and an aliquot of bromo-pyridin-3-yl-aceticacid ethyl ester (approx. 3.6 g; 15 mmol) in DMF (20 mL). Columnchromatographic purification over SiO₂ (1% methanol/chloroform) produceda yellow/orange oil (320 mg; approx. 8% yield). MS(ES)₇calc'd:[M+H]⁺=259.2 m/z. Found: 259.1 m/z.

Preparation 3995-(3-Amino-cyclohexyl)-9-chloro-3-methyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-one

[0824] A solution of a compound from preparation 379 (0.150 g, 0.39mmol) in CH₂Cl₂ (20 mL) was treated with TMSI (0.116 g, 0.58 mmol) andstirred at rt. for 6 hr. The reaction was then treated with MeOH (5 mL)and stirred for an additional 20 min. The solution was concentrated toan oil and then ether was added. The solid was filtered to afford 0.095g (74%) of the title compound as an orange solid. MS (ES+) m/z 331.2(M+H)⁺.

Preparation 4003-(2-Chloro-6-fluoro-phenyl)-3-oxo-2-(triphenyl-15-phosphanylidene)-propionicacid ethyl ester

[0825] To a solution of 20.0 g (0.115 mol) of 2-chloro-6-fluorobenzoicacid in 150 ml methylene chloride and 0.50 mL of DMF was added 11.0 mL(0.126 mol) oxalyl chloride, dropwise at rt. over 15 minutes. Thereaction was stirred at rt. for one hour and concentrated in vacuo. Theresulting acid chloride was redissolved in 50 mL of toluene. In aseparate flask, 34.0 mL (0.138 mol) of bis(trimethylsilyl) acetamide wasdissolved in 300 mL of toluene. To this was added 40.0 g (0.115 mol) of(carbethoxymethylene)-triphenylphosphorane. The resulting suspension wascooled to 10° C. and stirred as3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride in 50mL of toluene was added dropwise. The cold bath was removed and thereaction was allowed to stir at rt. for 18 hours. The mixture wasconcentrated in vacuo and to the resulting solid was added 50 mL oftoluene. The white solid was collected by vacuum filtration to give 49.0g (84%) of the title compound. MS(ES+) (m/z) 505.1 [M+1].

Preparation 401 3-(2-Chloro-6-fluoro-phenyl)-2,3-dioxo-propionic acidethyl ester

[0826] A solution of 25.0 g (49.5 mmol) of the compound from preparation400 in 125 mL of methylene chloride was cooled to −78° C. Into thecooled solution was passed ozone, prepared using an ozone generator(Griffin Tech. Corp.) and oxygen at 1.8 amps. The ozone was bubbledthrough the cooled solution using a gas dispersion tube. The reactionwas monitored visually, and determined to be completed after 45 minutes,due to the characteristic blue color that is associated with an ozonesaturated solution of methylene chloride. The reaction was purged withnitrogen gas and warmed to rt. The organic solution was washed twicewith brine, dried over sodium sulfate and concentrated in vacuo. Thiscrude material was purified by flash chromatography (silica gel, 50%hexanes-ethyl acetate) to give 13.0 g (98%) of the title compound as ayellow oil. Anal. Calcd. for C₁₁H₈O₄Cl: C, 51.08; H. 3.12. Found: C,50.67; H. 3.12.

Preparation 402 5-(2-Chloro-6-fluoro-phenyl)₃H-imidazole-4-carboxylicacid ethyl ester

[0827] A solution containing 6.80 g (26.0 mmol) of a compound frompreparation 401 in 50 mL of glacial acetic acid was added to a slurry of20.3 g (260 mmol) of ammonium acetate in 100 mL of glacial acetic acid.To this mixture was added 3.95 g (130 mmol) of paraformalehyde. Themixture was stirred and heated at 80° C. for one hour and concentratedin vacuo. The resulting crude material was taken up in ethyl acetate andwashed with saturated sodium bicarbonate (3×). The organic solution wasdried over sodium sulfate and concentrated in vacuo to give an oilyyellow solid. This crude material was precipitated out of 50% ethylacetate-hexane to give 3.35 g (48%) of the title compound as a lightyellow amorphous solid. MS (ES+) (m/z) 269.0 [M+1].

Preparation 403 & 4045-(2-Chloro-6-fluorophenyl)-3-methyl-3H-imidazole-4-carboxylic acidethyl ester (isomer 1)5-(2-Chloro-6-fluorophenyl)-1-methyl-1H-imidazole-4-carboxylic acidethyl ester (isomer 2)

[0828] To a solution containing 2.90 g (10.8 mmol) of the compound frompreparation 402 in 15 mL of DMF was added 2.98 g (21.6 mmol) of solidanhydrous potassium carbonate, followed by 1.34 mL (21.6 mmol) of methyliodide, with stirring, at rt. The reaction was stirred at rt. for onehour, diluted with 100 mL of ethyl acetate and washed four times withbrine. The resulting crude material was purified by flash chromatography(silica gel, hexanes-ethyl acetate gradient) and two main products wereseparated. The major product contained 1.62 g (53%) and was identifiedas the title compound (isomer 1). The isomeric minor product, which wasidentified as the title compound (isomer 2) was found to contain 933 mg(31%).

[0829] isomer 1: Mass spectrum (ES+) (m/z) 283.0 [M+1].

[0830] Anal. Calcd. for C₁₃H₁₂N₂O₂FCl: C, 55.23; H, 4.28; N, 9.91.Found: C, 55.14; H, 4.26; N, 9.75.

[0831] isomer 2: Mass spectrum (ES+) (m/z) 283.0 [M+1].

[0832] Anal. Calcd. for C₁₃H₁₂N₂O₂FCl: C, 55.23; H, 4.28; N, 9.91.Found: C, 55.08; H, 3.96; N, 9.77.

Preparation 4055-(2-Chloro-6-fluoro-phenyl)-3-methyl-3H-imidazole-4-carboxylic acid

[0833] To a solution of 95 mg (0.336 mmol) of a compound frompreparation 403. in 5 mL methanol was added 5 mL of 1N sodium hydroxidesolution. The reaction was stirred at rt. for 18 hours. The pH of thereaction was adjusted to pH ˜1 with 1N HCl and this material wasconcentrated in vacuo by adding 100 mL of toluene to aid in theazeotropic removal of water. The subsequent white solid, which containedthe free acid. The crude title compound was used without furtherpurification.

[0834] General Procedures, Unless Otherwise Specified:

[0835] a) For Condensation of a Primary Amine with a Carboxylic Acid

[0836] To “Starting Material A,” the primary amine of interest (1 eq.),in anhydrous DMF at 0° C. was added “Starting Material B,” thecarboxylic acid (3 eq.), collidine (3 eq.) and BOP (3 eq.). The coldbath was removed and after 2 h. The reaction was diluted with EtOAc (25mL) and saturated NaHCO₃ (25 mL). The organic layer was washed withdistilled H₂O (2×25 mL), dried over Na₂SO₄, and chromatographed onsilica gel.

[0837] b) For Acylation of Primary Amines

[0838] To a solution of “Starting Material A,” the primary amine (1eq.), in dichloromethane was added “Starting Material B,” the acylatingreagent (1 eq.), triethylamine (1 eq.), and 4-dimethylaminopyridine (10%mol.eq.). The mixture was stirred overnight at ambient temperature andchloroform was added. The solution was washed with 1N hydrochloric acid,saturated sodium bicarbonate, then brine; dried over sodium sulfate,filtered, and the solvent was removed in vacuo. The residue waschromatographed on silica gel to afford the desired compound.

[0839] c) For Coupling of Primary Amines and Carboxylic Acids, Using1-(3-(dimethylamino)-propyl)3-ethylcarbodiimide HCl (EDC)

[0840] To a solution of “Starting Material A,” the carboxylic acid (1eq.), in N,N-dimethylformamide was added “Starting Material B,” theprimary amine (1 eq.), along with EDC (1 eq.),1-hydroxy-7-azabenzotriazole (1 eq.), 4-dimethylaminopyridine (10% mol.eq.), and triethylamine (1 eq.). The mixture was stirred overnight atambient temperature and concentrated to dryness. The residue waspartitioned between 20% isopropanol/chloroform and 1N hydrochloric acid.The mixture was washed with 1N hydrochloric acid, saturated sodiumbicarbonate, brine, dried over sodium sulfate, filtered and concentratedto dryness. The residue was chromatographed on silica gel.

[0841] d) For Cyclization of2-((1R,3S)-3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonylamino}cycloalkylCompounds Using Potassium t-butoxide (KOtBu)

[0842] A solution of “Starting Material” (1 eq.) and 1 eq. of 1.0 N (inTHF) KOtBu in DMF was stirred for 3 hours. The reaction was diluted withethyl acetate and washed 5 times with water; dried and concentrated invacuo to a residue, which was chromatographed on silica gel.

[0843] e) For Cyclization of2-(3-{[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]-carbonylamino}cycloalkylCompounds Using Potassium bis(trimethylsilyl)amide (KHMDS)

[0844] A solution of “Starting Material” (1 eq.) dissolved in dry DMFwas stirred and cooled to 0° C. in an ice bath. The reaction was thentreated with KHMDS (1.5 eq., 0.5M in THF) and was allowed to warm toroom temperature. After 30 minutes the reaction was diluted in EtOAc,transferred to a separatory funnel, and washed consecutively with 1NHCl, saturated sodium bicarbonate, brine and dried over sodium sulfate.The solvent was removed in vacuo and the residue was chromatographed onsilica gel to afford the desired compound.

[0845] f) For Arylation of a Primary Amine

[0846] To a stirred solution of “Starting Material A,” the primary amine(1 eq.), in DMF was added K₂CO₃ (2 eq.) and “Starting Material B,” thearylhalide (3 eq.). The reaction mixture was stirred at 50° C. for 8hours. It was diluted with ethyl acetate, washed (brine), dried(Na₂SO₄), filtered and concentrated. Column chromatography on silica gelfor purification was preformed.

[0847] g) Enantiomeric Separation of the 1R,3S and 1S,3R IsomerConfiguration of the Cycloalkyl Examples

[0848] The racemic material was separated into its enantiomers by chiralHPLC, using a Chiralpak AD column and 30% isopropyl alcohol-heptane asthe eluent at a flow of 1.0 mL/min. a) Table for condensation usingcollidine: Ex. Starting # Product Material A Starting Material BPhysical Data 1cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 69phenylacetic acid ESIMS m/e 450 ³⁵Cl (M⁺ + 1)yl)-3-[(phenylmethylcarbonyl)amino]cyclohexane and 452 ³⁷Cl (M⁺ + 1) 2cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 693-methoxy- ESIMS m/e 480 ³⁵Cl (M⁺ + 1)yl)-3-[(3-methoxyphenyl)methyl]carbonyl]amino]cyclohexane phenylaceticacid and 482 ³⁷Cl (M⁺ + 1) 3cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 692-(4-fluorophenyl)- ESIMS m/e 468 ³⁵Cl (M⁺ + 1)yl)-3-[(4-fluorophenyl)methyl]carbonyl]amino]cyclohexane acetic acid and470 ³⁷Cl (M⁺ + 1) 4cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 692-(4- ESIMS m/e 480 ³⁵Cl (M⁺ + 1)yl)-3-[(4-methoxyphenyl)methyl]carbonyl]amino]cyclohexanemethoxyphenyl)- and 482 ³⁷Cl (M⁺ + 1) acetic acid 5cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 692-(2- ESIMS m/e 480 ³⁵Cl (M⁺ + 1)yl)-3-[(2-methoxyphenyl)methyl]carbonyl]amino]cyclohexanemethoxyphenyl)- and 482 ³⁷Cl (M⁺ + 1) acetic acid 6cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 692-(2-fluorophenyl)- ESIMS m/e 468 ³⁵Cl (M⁺ + 1)yl)-3-[(2-fluorophenyl)methyl]carbonyl]amino]cyclohexane acetic acid and470 ³⁷Cl (M⁺ + 1) 7cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 692-(3-fluorophenyl)- ESIMS m/e 502 ³⁵Cl (M + ³⁵Cl⁻)yl)-3-[(3-fluorophenyl)methyl]carbonyl]amino]cyclohexane acetic acid and504 ³⁷Cl (M + ³⁵Cl⁻) 8cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 692-(2-pyridyl)acetic ESIMS m/e 451 ³⁵Cl (M⁺ + 1)yl)-3-[(pyrid-2-yl)methyl]carbonyl]amino]cyclohexane acid and 453 ³⁷Cl(M⁺ + 1) 9 cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-prep 69 2-(3-pyridyl)acetic ESIMS m/e 451 ³⁵Cl (M⁺ + 1)yl)-3-[(pyrid-3-yl)methyl]carbonyl]amino]cyclohexane acid and 453 ³⁷Cl(M⁺ + 1) 10 (1S,3R)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep68 (2S)-2-[(t-butoxy)- ESIMS m/e 565 ³⁵Cl (M⁺ + 1)quinolin-5-yl)-3-{[(2S)-2-[[(1,1-dimethylethyloxy)carbonyl]-carbonylamino]-2- and 567 ³⁷Cl (M⁺ + 1)amino]-2-(phenyl)acetyl]amino}cyclohexane phenylacetic acid 11(1R,3S)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 69(2R)-2-[(t-butoxy)- ESIMS m/e 565 ³⁵Cl (M⁺ + 1)quinolin-5-yl)-3-[[(2R)-2-[[(1,1-dimethylethyloxy)carbonyl]-carbonylamino]-2- and 567 ³⁷Cl (M⁺ + 1)amino]-2-(phenyl)acetyl]amino]cyclohexane phenylacetic acid 12(1R,3S)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 69(2S)-2-[(t-butoxy)- ESIMS m/e 565 ³⁵Cl (M⁺ + 1)quinolin-5-yl)-3-[[(2S)-2-[[(1,1-dimethylethyloxy)carbonyl]-carbonylamino]-2- and 567 ³⁷Cl (M⁺ + 1)amino]-2-(phenyl)acetyl]amino]cyclohexane phenylacetic acid 13(1S,3R)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 68(2R)-2-[(t-butoxy)- ESIMS m/e 565 ³⁵Cl (M⁺ + 1)quinolin-5-yl)-3-[[(2R)-2-[[(1,1-dimethylethyloxy)carbonyl]-carbonylamino]-2- and 567 ³⁷Cl (M⁺ + 1) amino]-2-(phenyl)acetyl]amino]cyclohexane phenylacetic acid

[0849] b) Table for Acylation: Starting Starting Ex. # Product MaterialA Material B Physical Data Comments 14N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 44cyclohexylcarbonyl MS (ion spray)c]quinolin-5-yl))cyclohexyl]methyl}cyclohexylcarboxamide chloride 456.2(M + 1) 15 N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-prep 44 biphenylcarbonyl MS (ion spray)quinolin-5-yl)cyclohexylmethyl](4-phenylphenyl)- chloride 526.2 (M+)carboxamide 16 N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-prep 44 acetic MS (ion spray) c]quinolin-5-yl)cyclohexylmethyl]acetamideanhydride 388 (M + 1) 17N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 44methanesulfonyl MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]methanesulfonamide chloride 424.0(M + 1) 18 N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep44 methyl MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]methoxycarboxamide chloroformate 404.0(M + 1). 19 N-[(1R,3S)-3-(methylaminothioxomethylaminomethyl) prep 44methyl MS (ion spray) cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,isothiocyanate 419.0 (M + 1) 3-c]quinolin-4-one 20N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 44isobutyryl MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-2-methylpropanamide chloride 416.1(M + 1) 21 N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep44 3- MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-3-methylthiopropanamidemethylthiopropionyl 448.1 (M + 1) chloride 22N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 44 valerylchloride MS (ion spray) c]quinolin-5-yl)cyclohexylmethyl]pentanamide430.2 (M + 1) 23 N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-prep 44 phenacetyl MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-2-phenylacetamide chloride 463.9(M + 1) 24 N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep44 hydrocinnamoyl MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-3-phenylpropanamide chloride 478. 1(M + 1) 25 2-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3-prep 47 MS (ion spray) prep. 47 wasc]quinolin-5-yl)cyclohexyl]-N-pyridin-3-ylacetamide amino- 451 (M + 1)converted to pyridine the acid chloride using oxalyl chloride in DCM 262-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 4- prep 47 MS(ion spray) prep. 47 wasc]quinolin-5-yl)cyclohexyl]-N-pyridin-4-ylacetamide amino- 451.2 (M + 1)converted to pyridine the acid chloride using oxalyl chloride in DCM 272-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2- prep 47 MS(ion spray) prep. 47 wasc]quinolin-5-yl)cyclohexyl]-N-thiazol-2-ylacetamide amino- 457.1 (M + 1)converted to thiazole the acid chloride using oxalyl chloride in DCM 282-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3-amino- prep 47MS (ion spray) prep. 47 wasc]quinolin-5-yl)cyclohexyl]-N-(3-hydroxyphenyl)acetamide phenol 466.2(M + 1) converted to the acid chloride using oxalyl chloride in DCM 29N-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 48 aceticMS (ion spray) c]quinolin-5-yl)cyclohexylmethyl]acetamide anhydride 388(M + 1) 30 N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-prep 48 pivaloyl MS (ion spray)quinolin-5-yl)cyclohexylmethyl]-2,2-dimethylpropionamide chloride 430.1(M + 1) 31 N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep48 cyclobutylcarbonyl MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-cyclobutyl carboxamide chloride 428(M + 1) 32 [(1R, 3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-prep 48 isoxazolecarbonyl MS (ion spray)quinolin-5-yl)cyclohexylmethyl]-isoxazol-5-yl carboxamide chloride 441.1(M + 1) 33 5-((1S,3R)-3-{[(Methylsulfonyl)amino]methyl}-9-chloro-3- prep48 methanesulfonyl MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-4-one chloride 424.1 (M + 1) 345-((1S,3R)-3-{[Phenylsulfonyl)amino]methyl}-9-chloro-3- prep 48benzenesulfonyl MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-4-one chloride 486.4 (M + 1) 35[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 48 phenylMS (ion spray) quinolin-5-yl)cyclohexylmethyl]phenoxycarboxamidechloroformate 466.2 (M + 1) 36[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- prep 48phenylisocyanate MS (ion spray)quinolin-5-yl)cyclohexylmethyl](phenyl-amino)carboxamide 464.9 (M+) 375-[(1S,3R)-3-(Phenylaminothiomethylamniomethyl)-cyclohexyl prep 48phenylthioisocyanate MS (ion spray)]-9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- 481.02 (M + 1)quinolin-4-one 38[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- prep 48morpholine MS (ion spray) quinolin-5-yl)cyclohexylmethyl]morpholin-4-ylcarboxamide carbonyl 459.2 (M + 1) chloride 39[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- prep 48cyclohexyl- MS (ion spray) quinolin-5-yl)cyclohexylmethyl]cyclohexylcarboxamide carbonyl 456.3 (M + 1) chloride 40[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- prep 48picolinoyl MS (ion spray) quinolin-5-yl)cyclohexylmethyl]pyridin-2-ylcarboxamide chloride HCl 450.9 (M + 1) 41N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 48nicotinoyl MS (ion spray) c]quinolin-5-yl)cyclohexylmethyl]nicotinamidechloride HCl 451.1 (M + 1) 42N-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 48isonicotinoyl MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]isonicotinamide chloride HCl 451.1(M + 1) 43 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazalo-[4,3-c]- prep 54benzoyl MS(FIA) m/z = 450 prep. 54 wasquinolin-5-yl)cyclohexylmethyl]benzamide chloride converted to theprimary amine using TFA in DCM 44N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- prep 543,4,5-Tri- MS(FIA) m/z = 540.4 prep. 54 was5-yl)cyclohexylmethyl]-3,4,5-trimethoxybenzamide methoxybenzoylconverted to chloride the primary amine using TFA in DCM 45N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- prep 544-Methoxybenzoyl MS(FIA) m/z = 480.1 prep. 54 wasquinolin-5-yl)cyclohexylmethyl]-4-methoxy-benzamide chloride convertedto the primary amine using TFA in DCM 46N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- prep 543-Methoxybenzoyl MS(FIA) m/z = 480.2 prep. 54 was5-yl)cyclohexylmethyl]-3-methoxy-benzamide chloride converted to theprimary amine using TFA in DCM 47N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- prep 544-Nitrobenzoyl MS(FIA) m/z = 493.2 prep. 54 was5-yl)cyclohexylmethyl]-4-nitrobenzamide chloride converted to theprimary amine using TFA in DCM 48N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- prep 543-Nitrobenzoyl MS(FIA) m/z = 495.1 prep. 54 was5-yl)cyclohexylmethyl]-3-nitrobenzamide chloride converted to theprimary amine using TFA in DCM 49N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- prep 54methyl 4- MS(FIA) m/z = 508.2 prep 54 was5-yl)cyclohexylmethyl]-4-carbomethoxybenzamide (chlorocarbonyl)converted to benzoate the primary amine using TFA in DCM 50N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- prep 54methyl 3- MS(FIA) m/z = 508.2 prep 54 was5-yl)cyclohexylmethyl]-3-carbomethoxybenzamide (chlorocarbonyl)converted to benzoate the primary amine using TFA in DCM 51N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- Ex 49 —MS(FIA) m/z = 492.2 prepared by5-yl)cyclohexylmethyl]-3-carboxybenzamide basic hydrolysis 52N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- Ex 50 —MS(FIA) m/z = 492.2 prepared by5-yl)cyclohexylmethyl]-3-carboxybenzamide basic hydrolysis 53N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 54 BenzoylMS(FIA) m/z = 450 prep. 54 wasquinolin-5-yl)-R-cyclohexylmethyl]benzamide chloride converted to theprimary amine using TFA in DCM 54N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 542-Methoxybenzoyl MS(FIA) m/z = 480.1 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2-methoxybenzamide chlorideconverted to the primary amine using TFA in DCM 55N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 543-Methoxybenzoyl MS(FIA) m/z = 480.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3-methoxybenzamide chlorideconverted to the primary amine using TFA in DCM 56N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 544-Methoxybenzoyl MS(FIA) m/z = 480.1 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-methoxybenzamide chlorideconverted to the primary amine using TFA in DCM 57N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 54 3-EthoxybenzoylMS(FIA) m/z = 494.3 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3-ethoxybenzamide chlorideconverted to the primary amine using TFA in DCM 58N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 54 4-Trifluoro-MS(FIA) m/z = 534.2 prep. 54 was quinolin-5-yl)-R-cyclohexylmethyl]-4-methoxybenzoyl converted to trifluoromethoxybenzamide the primarychloride amine using TFA in DCM 59N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 54 4-EthoxybenzoylMS(FIA) m/z = 494.3 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-ethoxybenzamide chlorideconverted to the primary amine using TFA in DCM 60N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 543,4-Dimethoxybenzoyl MS(FIA) m/z = 570.3 prep. 54 wasquinolin-5-yl)-R-cyclohexylmethyl]-3,4-dimethoxy-benzamide chlorideconverted to the primary amine using TFA in DCM 61N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 543,4-methylene- MS(FIA) m/z = 494.2 prep. 54 wasquinolin-5-yl)-R-cyclohexylmethyl]-3,4-methylenedioxy- dioxybenzoylconverted to benzamide chloride the primary amine using TFA in DCM 62N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 54 2- MS(FIA) m/z= 468.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2-fluorobenzamide Fluorobenzoylconverted to chloride the primary amine using TFA in DCM 63N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 54 3- MS(FIA) m/z= 468.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3-fluorobenzamide Fluorobenzoylconverted to chloride the primary amine using TFA in DCM 64N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 54 4- MS(FIA) m/z= 468.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-fluorobenzamide Fluorobenzoylconverted to chloride the primary amine using TFA in DCM 65N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 542,3-Difluorobenzoyl MS(FIA) m/z = 486.4 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2,3-difluorobenzamide chlorideconverted to the primary amine using TFA in DCM 66N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 542,4-Difluorobenzoyl MS(FIA) m/z = 486.5 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2,4-difluorobenzamide chlorideconverted to the primary amine using TFA in DCM 67N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 542,5-Difluorobenzoyl MS(FIA) m/z = 486.4 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2,5-difluorobenzamide chlorideconverted to the primary amine using TFA in DCM 68N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 542,6-Difluorobenzoyl MS(FIA) m/z = 486.6 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2,6-difluorobenzamide chlorideconverted to the primary amine using TFA in DCM 69N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 543,4-Difluorobenzoyl MS(FIA) m/z = 486.4 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3,4-difluorobenzamide chlorideconverted to the primary amine using TFA in DCM 70N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 543,5-Difluorobenzoyl MS(FIA) m/z = 486.4 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3,5-difluorobenzamide chlorideconverted to the primary amine using TFA in DCM 71N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- prep 543,4,5-Trifluorobenzoyl MS(ES+) m/z = 504.1 prep. 54 wasquinolin-5-yl)-R-cyclohexylmethyl]-3,4,5-trifluorobenzamide chlorideconverted to the primary amine using TFA in DCM 72N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 2- MS(FIA) m/z= 484.4 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2-chlorobenzamide Chlorobenzoylconverted to chloride the primary amine using TFA in DCM 73N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 3- MS(FIA) m/z= 484.4 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3-chlorobenzamide Chlorobenzoylconverted to chloride the primary amine using TFA in DCM 74N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4- MS(FIA) m/z= 484.4 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-chlorobenzamide Chlorobenzoylconverted to chloride the primary amine using TFA in DCM 75N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 3- MS(FIA) m/z= 530.0 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3-bromobenzamide Bromobenzoylconverted to chloride the primary amine using TFA in DCM 76N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4- MS(FIA) m/z= 530.0 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-bromobenzamide Bromobenzoylconverted to chloride the primary amine using TFA in DCM 77N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4-IodobenzoylMS(FIA) m/z = 576.1 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-iodobenzamide chloride convertedto the primary amine using TFA in DCM 78N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 2- MS(FIA) m/z= 464.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2-methylbenzamide Methylbenzoylconverted to chloride the primary amine using TFA in DCM 79N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 3- MS(FIA) m/z= 464.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3-methylbenzamide Methylbenzoylconverted to chloride the primary amine using TFA in DCM 80N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4- MS(FIA) m/z= 464.2 prep. 54 wasc]quinolin-5-yl-R-cyclohexylmethyl]-4-methylbenzamide Methylbenzoylconverted to chloride the primary amine using TFA in DCM 81N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- prep 543-Trifluoromethyl- MS(FIA) m/z = 518.2 prep. 54 wasquinolin-5-yl)-R-cyclohexylmethyl]-3-trifluoromethyl- benzoyl convertedto benzamide chloride the primary amine using TFA in DCM 82N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4-Trifluoro-MS(FIA) prep. 54 was c]quinolin-5-yl)-R-cyclohexylmethyl]-4-methylbenzoyl m/z = 518.2 converted to trifluoromethylbenzamide chloridethe primary amine using TFA in DCM 83N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4- MS(ES+) m/z= 526.0 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-phenylbenzamide phenylbenzoylconverted to chloride the primary amine using TFA in DCM 84N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4-t- MS(FIA)m/z = 506.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-t-butylbenzamide Butylbenzoylconverted to chloride the primary amine using TFA in DCM 85N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4- MS(ES+) m/z= 474.9 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-4-cyanobenzamide Cyanobenzoylconverted to chloride the primary amine using TFA in DCM 86N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 2,6-Dimethyl-MS(FIA) m/z = 478.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2,6-dimethylbenzamide benzoylconverted to chloride the primary amine using TFA in DCM 87N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 3-Dimethyl-MS(FD) m/z = 492.2 prep. 54 was c]quinolin-5-yl)-R-cyclohexylmethyl]-3-amino benzoyl converted to dimethylaminobenzamide chloride the primaryamine using TFA in DCM 88N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 4-Dimethyl-MS(FIA) m/z = 493.2 prep. 54 was c]quinolin-5-yl)-R-cyclohexylmethyl]-4-aminobenzoyl converted to dimethylaminobenzamide chloride the primaryamine using TFA in DCM 89N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 naphthalene-1-MS(FIA) m/z = 500.1 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-1-naphthylcarboxamide carbonylconverted to chloride the primary amine using TFA in DCM 90N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 naphthalene-2-MS(FIA) m/z = 500.1 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2-naphthylcarboxamide carbonylconverted to chloride the primary amine using TFA in DCM 91N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 2-FuroylMS(FIA) m/z = 440.2 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-2-furylcarboxamide chlorideconverted to the primary amine using TFA in DCM 92N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3- prep 54 2-ThiopheneMS(FIA) m/z = 456.3 prep. 54 was c]quinolin-5-yl)-R-cyclohexylmethyl]-2-carbonyl converted to thiophenylcarboxamide chloride the primary amineusing TFA in DCM 93 N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-prep 54 3-Thiophene MS(FIA) m/z = 456.3 prep. 54 wasc]quinolin-5-yl)-R-cyclohexylmethyl]-3- carbonyl converted tothiophenylcarboxamide chloride the primary amine using TFA in DCM 94N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- Ex 567acetyl chloride MS(FIA) m/z = 507.25-yl)-cyclohexylmethyl]-3-acetylaminobenzamide 95N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- Ex 567methanesulfonyl MS(FIA) m/z = 621.4quinolin-5-yl)cyclohexylmethyl]-3-bis-(methanesulfonyl)- chlorideaminobenzamide 96N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- prep 64benzoyl MS (ion spray) prep 64 was5-yl)-2,2-dimethylcyclobutyl-methyl]benzamide chloride 450 (M⁺), 448converted to (M⁻ − 1) the amine by TBAF in DCM at rt. 97N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- prep 64phenylacetyl MS (ion spray) prep 64 was5-yl)-2,2-dimethylcyclobutyl-methyl]-2-phenylacetamide chloride 464(M⁺), 462 converted to (M⁻ − 1) the amine by TBAF in DCM at rt. 98N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- prep 643,4,5-tri- MS (ion spray) prep 64 was5-yl)-2,2-dimethylcyclobutyl-methyl]-3,4,5- methoxybenzoyl 540 (M⁺), 548converted to trimethoxybenzamide chloride (M⁻ − 1) the amine by TBAF inDCM at rt. 99N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- prep 68benzoyl MS (ion spray) 5-yl)cyclohexyl]benzamide chloride 436 (M⁺) 100N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- prep 69benzoyl MS (ion spray) 5-yl)cyclohexyl]benzamide chloride 436 (M⁺) 101N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- prep 68phenacetyl MS (ion spray) 5-yl)cyclohexyl]-2-phenylacetamide chloride450.1 (M + 1) 102N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- prep 69phenacetyl MS (ion spray) 5-yl)cyclohexyl]-2-phenylacetamide chloride450.1 (M + 1) 103 Phenyl-carbamic acid 3-(9-chloro-3-methyl-4-oxo-5H-prep 85 phenyl MS(ES):(M + 1)⁺isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl ester isocyanate 466.2m/z 104 N-{2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]- prep 93trimethylacetyl MS(ES) [M + H]⁺ =quinolin-5-yl)cyclohexyl]ethyl}-2,2-dimethyl-N-phenyl- chloride 520.2367m/z propionamide 105 9-Chloro-5-{3-[3-chloro-1-oxo-butylamino)-methyl]-prep 48 4-chlorobutyryl MS(FIA) (m/z)cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one chloride 450.1(M + 1) 106 N-[3-(9-Iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-5-Ex 594 benzoyl MS (FIA) (m/z) Ex 594 was yl)-cyclohexylmethyl]-benzamidechloride 542.3 [M + 1] converted to the primary amine using TFA in DCM107 N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin- prep 146phenylsulfonyl MS (ion spray) 5-yl)-cyclohexylmethyl]-benzenesulfonamidechloride 486 (M⁺), 484 (M⁻ − 1) 108N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin- prep 146nicotinoyl MS (ion spray) 5-yl)-cyclohexylmethyl]nicotinamide chlorideHCl 451 (M⁺), 449 (M⁻ − 1) 109N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin- prep 146m-anisoyl MS (ion spray) 5-yl)-cyclohexylmethyl]-3-methoxybenzamidechloride 480 (M⁺), 478 (M⁻ − 1) 110 Pyridine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H- prep 146 picolinoyl MS (ion spray)isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]amide chloride HCl 451(M⁺), 449 (M⁻ − 1) 111N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 146 4-MS (ion spray) 5-yl)cyclohexylmethyl]-4-fluorobenzamide fluorobenzoyl468 (M⁺), 466 chloride (M⁻ − 1) 112N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 146 3-MS (ion spray) 5-yl)cyclohexylmethyl]-3-fluorobenzamide fluorobenzoyl468 (M⁺), 466 chloride (M⁻ − 1) 113 Thiophene-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H- prep 146 2-thiophene- MS (ion spray).isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]amide carbonyl 456 (M⁺),454 chloride (M⁻ − 1) 114N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin- prep 146isonicotinoyl MS (ion spray) 5-yl)cyclohexylmethyl]isonicotinamidechloride HCl 451 (M⁺), 449 (M⁻ − 1) 115N-{[(1R,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 1462-furoyl MS (ion spray)c]quinolin-5-yl))cyclohexyl]methyl}-2-furylcarboxamide chloride 440(M⁺), 438 (M⁻ − 1) 116N-{[(1R,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 146phenylacetyl MS (ion spray)c]quinolin-5-yl))cyclohexyl]-methyl}-2-phenylacetamide chloride 440(M⁺), 438 (M⁻ − 1) 117cis-3-(benzoylamino)-1-(9-chloro-3-methyl-4-oxo-5H- prep 146benzoylchloride ESIMS m/e 436 isoxazolo[4,3-c]quinolin-5-yl)cyclohexane³⁵Cl (M⁺ + 1) & 438 ³⁷Cl (M⁺ + 1) 118N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo-[4,5-c]quinolin- Ex 612benzoyl MS (+ES)m/z 5-yl)cyclohexylmethyl]benzamide chloride 450.0 (M +H)+ 119 (1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5- Ex 6134- MS (ES+) m/z c]quinolin-5-yl)-cyclohexylmethyl]-4-fluorobenzamidefluorobenzoyl 468.0 (M + H)⁺ chloride 120 (1R,3S)-Thiophene-2-carboxylicacid [3-(9-chloro-3-methyl-4- Ex 613 2-Thiophene- MS (ES+) m/zoxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl]- carbonyl 456.0(M + H)⁺ amide chloride 121(1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5- Ex 614 benzoylMS (ES+) m/z c]quinolin-5-yl)cyclohexylmethyl]benzamide chloride 450.0(M + H)⁺ 122 (1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5- Ex614 4- MS (ES+) m/z c]quinolin-5-yl)cyclohexylmethyl]-4-fluorobenzamideFluorobenzoyl 468.0 (M + H)⁺ chloride 123 (1S,3R)-Thiophene-2-carboxylicacid [3-(9-chloro-3-methyl-4- Ex 614 2-thiophene- MS (ES+) m/zoxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl]- carbonyl 455.9(M + H)⁺ amide chloride 124(1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5- Ex 614nicotinoyl MS (ES+) m/z c]quinolin-5-yl)cyclohexylmethyl]nicotinamidechloride 451.0 (M + H)⁺ 125(1R,3S)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5- Ex 615 benzoylMS (ES+) m/z c]quinolin-5-yl)cyclohexylmethyl]benzamide chloride 500.1(M + H)⁺ 126 (1R,3S)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5- Ex615 nicotinyl MS (ES+) m/z c]quinolin-5-yl)cyclohexylmethyl]nicotinamidechloride 451.0 (M + H)⁺ 127N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin- Ex 616nicotinoyl MS (ES+) m/z 5-yl)cyclohexylmethyl]nicotinamide chloride451.0 (M + H)⁺ 128N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin- Ex 617nicotinoyl MS (ES+) m/z 5-yl)cyclohexylmethyl]nicotinamide chloride451.0 (M + H)⁺ 129N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 6193,4-difluoro- ESMS: 472c]quinolin-5-yl)cyclopentylmethyl]-3,4-difluorobenzamide benzoyl (m +1)⁺ chloride 130 N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-Ex 620 3-methoxy- ESMS: 466c]quinolin-5-yl)cyclopentylmethyl]-3-methoxybenzamide benzoyl (M + 1)⁺chloride 131 Thiophene-2-carboxylic acid (1S,3R)-3-(9-chloro-3-methyl-4-Ex 620 2-thiophene- ESMS: 442oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentylmethyl]- carbonyl (M +1)⁺ amide chloride 132(1S,3R)-3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4- Ex 6202-Chloro-6- ESMS: 569 carboxylic acid [3-(9-chloro-3-methyl-4-oxo-5H-fluorobenzoyl (M + 1)⁺isoxazolo[4,3-c]quinolin-5-yl)cyclopentylmethyl]amide chloride 133Pyrazine-2-carboxylic acid [(1S,3R)-3-(9-chloro-3-methyl-4- Ex 6202-pyrazine- ESMS: 438oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentylmethyl]- carbonyl (M +1)⁺ amide chloride 134N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 620(2S)-2-[(t- ESMS: 565c]quinolin-5-yl)cyclopentylmethyl]carbamoylphenylmethyl-butoxy)carbonylamino]- (M + 1)+ carbamic acid t-butyl ester 2-phenylacetic acid 135 2-Amino-N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-Ex 620 (2S)-2-amino- ESMS: 465isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylmethyl]-2- 2-phenylacetic (M +1)+ phenylacetamide acid 136N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 620 benzoylESMS: 436 c]quinolin-5-ylmethyl)cyclopentyl]benzamide chloride (M + 1)+137 N-{(1S,3R)-3-[(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 6203,4,5-tri- ESMS: 526 c]quinolin-5-yl))-methyl]cyclopentyl}(3,4,5-methoxybenzoyl (M + 1)+ trimethoxyphenyl)carboxamide chloride 138N-{(1R,3S)-3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole- Ex 6212-chloro-5- ESMS: 570 4-carboxylic acid [3-(9-chloro-3-methyl-4-oxo-5H-fluoro phenyl (M + 1)+isoxazolo[4,3-c]quinolin-5-ylmethyl)cyclopentyl]amide isoxazoyl chloride139 N-{(1R,3S)-3-[(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 6213,4,5- ESMS: 526 c]quinolin-5-yl))methyl]cyclopentyl}-(3,4,5-trimethoxybenzoyl (M + 1)+ trimethoxyphenyl)carboxamide chloride 140N-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 621 4- ESMS:454 c]quinolin-5-ylmethyl)cyclopentyl]-4-fluorobenzamide fluorobenzoyl(M + 1)+ chloride 141N-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 6213,4-difluoro- ESMS: 472c]quinolin-5-ylmethyl)-cyclopentyl]-3,4-difluorobenzamide benzoyl (M +1)+ chloride 142 N-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-Ex 621 pyridine-3- ESMS: 437c]quinolin-5-ylmethyl)cyclopentyl]nicotinamide carbonyl (M + 1)+chloride 143 N-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex621 3-methoxy- ESMS: 466c]quinolin-5-ylmethyl)cyclopentyl]-3-methoxybenzamide benzoyl (M + 1)+chloride 144 N-{[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex621 L-N-trifluoroacetyl ESMS: 561c]quinolin-5-ylmethyl)cyclopentylcarbamoyl]phenylmethyl} acetyl phenyl(M + 1)+ carbamic acid t-butyl ester glycine 1451-Acetyl-2,3-dihydro-1H-indole-2-carboxylic acid [3-(9- ((2S) acetic MS(ion spray) 519 chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-indolin-2- anhydride (M⁺). yl)-cyclohexyl]amide yl)-N- [(1R,3S)- 3-(9-chloro-3- methyl-4- oxo-5H- isoxazolo- [4,3-c] quinolin- 5-yl))cyclohexyl ]- carbox- amide 146N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5- Ex 624α-toluene- MS (ion spray) yl)-cyclohexyl]-C-phenylmethane sulfonamidesulfonyl 486 (M⁺). chloride 147(cis){N-[(cis)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 470nicotinoyl MS (ion spray)c]quinolin-5-yl))cyclohexyl]-carbamoyl}phenylmethyl pyridine- HCl 571(M⁺). 3-carboxylate 148(trans){N-[(cis)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 471nicotinoyl MS (ion spray)c]quinolin-5-yl))cyclohexyl]-carbamoyl}phenylmethyl pyridine- HCl 571(M⁺). 3-carboxylate 149N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]-quinolin-5- Ex 6326-Fluoro- MS m/z (ES+) 6-Fluoro-yl)-cyclohexylmethyl]-6-fluoro-nicotinamide nicotinic 468.8 (M + H)⁺nicotinic acid acid was converted to the acid chloride by oxalylchloride in DCM. 1506-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5- Ex 6326-Chloronicotinic MS m/z (ES+) 6-c]quinolin-5-yl)cyclohexylmethyl]-nicotinamide acid 468.8 (M + H)⁺Chloronicotinic acid was converted to the acid chloride by oxalylchloride in DCM. 151N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5- Ex 633methanesulfonyl MS(ES): (M + 1)⁺yl)cyclohexyl]-2-methanesulfonylamino-2-phenylacetamide chloride 543.0,545.0 m/z 152N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5- Ex 251acetic MS (ion spray) yl)-cyclohexylmethyl]-5-diacetylamino-nicotinamideanhydride 550.2 (M+). 1536-Acetylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H- Ex 245 acetic MS (ionspray) isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-nicotinamideanhydride 508.2 (M+) 154N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5- Ex 632hydrocinnamoyl MS (ion spray) yl)cyclohexylmethyl]-3-phenylpropionamidechloride 478.1 (M+). 155[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5- Ex 634phenyl MS (ion spray) yl)cyclohexyl]carbamic acid phenyl esterchloroformate 451.96 (M+). 1561-Benzyl-3-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 634 benzylMS (ion spray) c]quinolin-5-yl)cyclohexyl]urea isocyanate 465.0 (M+) 1571-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex 634phenyl MS (ion spray) yl)cyclohexyl]-3-phenylthiourea isothiocyanate467.0 (M+) 1581-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex 634phenyl MS (ion spray) yl)cyclohexyl]-3-phenylurea isocyanate 451.96(M+). 159 N-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-prep 243 pivaloyl MS(ES) exact yl)cyclohexylcarbamoyl]phenylmethyl}-2,2-chloride mass [M] = dimethylpropionamide 548.2190 m/z 160N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex 638methanesulfonyl MS(ES) [M + H]⁺ =yl)cyclohexyl]-2-methanesulfonylamino-2-phenyl-acetamide chloride 543.1m/z 161 Morpholine-4-carboxylic acid {[3-(9-chloro-3-methyl-4-oxo- Ex638 morpholine-4- MS(ES) [M] =5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]- carbonyl 577.2092m/z. phenylmethyl}amide chloride 162N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin- Ex 640pivaloyl MS(ES) [M + H]⁺ =5-yl)cyclohexylcarbamoyl]pyridin-3-ylmethyl}-2,2-dimethyl- (isomer 1)chloride 550.2253 m/z. propionamide (isomer 1) 163N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex 640pivaloyl MS(ES) exactyl)-cyclohexylcarbamoyl]-pyridin-3-yl-methyl}-2,2-dimethyl- (isomer 2)chloride mass [M + H]⁺ = propionamide (isomer 2) 550.2247 m/z. 164N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]-quinolin-5- Ex 6326-Fluoro- MS m/z (ES+) 6- yl)cyclohexylmethyl]-6-fluoronicotinamidenicotinic 468.8 (M + H)⁺ Fluoronicotinic acid acid was converted to theacid chloride by oxalyl chloride in DCM. 165N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]-quinolin-5- Ex 6325-Fluoro- MS m/z (ES+) 5-Fluoro-yl)cyclohexylmethyl]-5-fluoronicotinamide nicotinic 468.8 (M + H)⁺nicotinic acid acid was converted to the acid chloride by oxalyl chloidein DCM. 166N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]-quinolin-5- Ex 525benzoyl MS(ES+) (m/z) Ex 525 was ylmethyl)cyclohexyl]benzamide chloride450.1 [M + 1] converted to the amine by TFA in DCM. 167N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]-quinolin-5- Ex 525 4-MS(ES+) (m/z) Ex 525 was ylethyl)cyclohexyl]-4-fluorobenzamidefluorobenzoyl 468.1 [M + 1] converted to chloride the amine by TFA inDCM. 168 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5- Ex525 3,4- MS(ES+) (m/z) Ex 525 was ylmethyl)cyclohexyl]benzamidedifluorobenzoyl 486.1 [M + 1]. converted to chloride the amine by TFA inDCM. 169 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5- Ex533 benzoyl MS(ES+) (m/z) Ex 533 was ylmethyl)cyclohexyl]benzamidechloride 450.1 [M + 1]. converted to the amine by TFA in DCM. 170N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]-quinolin-5- Ex 533 4-MS(ES+) (m/z) Ex 533 was ylmethyl)-cyclohexyl]-4-fluoro-benzamidefluorobenzoyl 468.1 [M + 1]. converted to chloride the amine by TFA inDCM. 171 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]-quinolin-5-Ex 533 3,4- MS(ES+) (m/z) Ex 533 wasylmethyl)cyclohexyl]-3,4-difluorobenzamide difluorobenzoyl 486.1 [M +1]. converted to chloride the amine by TFA in DCM. 172N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex 532nicotinoyl MS(ES+) (m/z) yl)cyclohexylmethyl]nicotinamide chloride 442.3[M + 1]. HCl 173N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex 540benzoyl MS(ES+) (m/z) Ex 540 was ylmethyl)cyclohexyl]benzamide chloride450.3 [M + 1]. converted to the amine by TFA in DCM. 174N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5- Ex 540 4-MS(ES+) (m/z) Ex 540 was ylmethyl)cyclohexyl]-4-fluorobenzamidefluorobenzoyl 468.0 [M + 1]. converted to chloride the amine by TFA inDCM. 175 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex540 3,4- MS(ES+) (m/z) Ex 540 wasylmethyl)cyclohexyl]-3,4-difluorobenzamide difluorobenzoyl 486.2 [M +1]. converted to chloride the amine by TFA in DCM. 176N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-quinolin-5- prep 360mesyl MS(ion spray) yl)cyclohexyl]bis(2-methanesulfonyl)amino-acetamidechloride 545.1 (M+) 177N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]-quinolin-5- prep 380benzoyl MS (ES+) m/z yl)cyclohexyl]benzamide chloride 436.1 (M + H)⁺,(ES−) 434.1 (M − H). 178 2-[(1R,3S)-3(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3,4- Prep 47 MS(ES+) m/z= 485.8 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(3,4-difluoro-phenyl)-acetamide difluoro-converted to aniline the acid chloride by oxalyl chloride in DCM. 1792-[(1R, 3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3,5- Prep 47MS(ES+) m/z = 486.1 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(3,5-difluoro-phenyl)-acetamide difluoroconverted to aniline the acid chloride by oxalyl chloride in DCM. 1802-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2-difluoro- Prep47 MS(ES+) m/z = 468.1 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(2-fluoro-phenyl)-acetamide anilineconverted to the acid chloride by oxalyl chloride in DCM. 1812-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- benzyl- Prep 47MS(ES+) m/z = 464.1 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-Benzyl-acetamide amnine converted to theacid chloride by oxalyl chloride in DCM. 1822-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3,4,5- Prep 47MS(ES+) m/z = 554.2 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(3,4,5-trimethoxy-benzyl)- Tri- convertedacetamide methoxy- to the benzyl- acid amine chloride by oxalyl chloridein DCM. 183 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2-Prep 47 MS(ES+) m/z = 480.1 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(2-methoxy-phenyl)-acetamide Methoxy-converted phenyl- to the amine acid chloride by oxalyl chloride in DCM.184 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 4- Prep 47MS(ES+) m/z = 480.1 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(4-methoxy-phenyl)-acetamide Methoxy-converted phenyl- to the amine acid chloride by oxalyl chloride in DCM.185 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2-Methyl-Prep 47 MS(ES+) m/z = 464.2 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(2-methyl-phenyl)-acetamide phenyl-converted amine to the acid chloride by oxalyl chloride in DCM. 1862-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3-Methyl- Prep47 MS(ES+) m/z = 464.1 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(3-methyl-phenyl)-acetamide phenyl-converted to amine the acid chloride by oxalyl chloride in DCM. 1872-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 4-Methyl- Prep47 MS(ES+) m/z = 464.1 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(4-methyl-phenyl)-acetamide phenyl-converted to amine the acid chloride by oxalyl chloride in DCM. 1882-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2,6- Prep 47MS(ES+) m/z = 478.2 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(2,6-dimethyl-phenyl)- Methyl- convertedto acetamide phenyl- the acid amine chloride by oxalyl chloride in DCM.189 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 4-Amino-Prep 47 MS(ES+) m/z = 508.2 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(4-carbomethoxy-phenyl)- benzoicconverted to acetamide acid the acid methyl chloride by ester oxalylchloride in DCM. 1902-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 6- Prep 47MS(ES+) m/z = 531.0 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-(6-methoxy-quinoline)- Methoxy- convertedto acetamide quinolin- the acid 8- chloride by ylamine oxalyl chloridein DCM. 191 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-Methyl- Prep 47 MS(ES+) m/z = 464.0 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-phenyl-N-methyl-acetamide phenyl-converted amine to the acid chloride by oxalyl chloride in DCM. 1922-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Methyl- Prep 47MS(ES+) m/z = 478.1 Prep 47 wasc]quinolin-5-yl)-cyclohexyl]-N-benzyl-N-methyl-acetamide benzyl-converted to amine the acid chloride by oxalyl chloride in DCM. 193(3-{[5-(2-Chloro-6-fluoro-phenyl)-3-methyl-3H-imidazole-4- Ex 615 prep405 MS (ES+) (m/z) Prep 405 wascarbonyl]-amino}-cyclohexylmethyl)-carbamic acid benzyl ester 499.2 [M +1] converted to the acid chloride by oxalyl chloride in DCM. 194N-[3-(9-Chloro-3-methyl-4-oxo-3,4-dihydro-imidazo[4,5- Ex 193 benzoyl MS(ES+) (m/z) Example 193 c]quinolin-5-yl)-cyclohexylmethyl]-benzamidechloride 449.2 [M + 1] was converted to the primary amine by TMSI inDCM. 195 1R, 3S-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 621benzoyl ESMS: 436 c]quinolin-5-ylmethyl)-cyclopentyl]-benzamide chloride(M + 1)⁺ 196 1R, 3S-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex621 phenylacetyl ESMS: 450c]quinolin-5-ylmethyl)-cyclopentyl-2-phenyl-acetamide chloride (M + 1)⁺197 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5- prep399 benzoyl MS (ES+) m/z yl)-cyclohexyl]-benzamide chloride 436.1 (M +H)⁺, (ES−) 434.1 (M − H)⁻ 198N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 390nicotinoyl MS (ion spray) yl)-cyclohexylmethyl]-N-methyl-nicotinamidechloride 465 (M⁺) HCl 199 R(−)Pyridine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H- Ex 471 picolinoyl MS (ion spray)isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-phenyl- chloride 571(M⁺) methyl ester HCl 200 R(−)Isonicotinic acid[3-(9-chloro-3-methyl-4-oxo-5H- Ex 471 isonicotinoyl MS (ion spray)isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl- chloride HCl571 (M⁺) methyl ester 201 S(+)Pyridine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo- Ex 470 picolinoyl MS (ion spray)5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]- chloride 571(M⁺) phenyl-methyl ester HCl 202 S(+)Isonicotinic acid[3-(9-chloro-3-methyl-4-oxo-5H- Ex 470 isonicotinoyl MS (ion spray)isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl- chloride 571(M⁺) methyl ester HCl

[0850] c) EDC Coupling: Starting Starting Ex. # Product Material AMaterial B Physical Data Comments 2039-Chloro-5-(3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]-2-oxo- prep 394-(4-fluoro- MS (ion spray)ethyl}cyclohexyl)-3-methyl-5H-isoxazolo[4,3-c]quinolin- benzoyl) 564.1(M+) 4-one piperidine HCl 2049-Chloro-3-methyl-5-[3-(2-morpholin-4-yl-2-oxoethyl)- prep 39 MorpholineMS (ion spray) cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one 444.2(M + 1) 205 9-Chloro-3-methyl-5-{3-[2-oxo-2-(4-phenylpiperazin-1- prep39 1-phenyl- MS (ion spray)yl)oxoethyl]cyclohexyl}-5H-isoxazolo[4,3-c]quinolin-4-one piperazine519.2 (M+) 2065-{3-[2-(4-Acetylpiperazin-1-yl)-2-oxoethyl]cyclohexyl}-9- prep 391-acetyl- MS (ion spray)chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one piperazine 485.3(M + 1) 207 2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-prep 39 cyclopropyl- MS (ion spray)5-yl)cyclohexyl]-N-cyclopropylacetamide amine 414.2 (M + 1) 2082-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 39cyclobutylamine MS (ion spray) 5-yl)cyclohexyl]-N-cyclobutylacetamide428.2 (M + 1) 2092-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 39Cyclopentyl- MS (ion spray) 5-yl)cyclohexyl]-N-cyclopentylacetamideamine 442.2 (M + 1) 2102-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 39Cyclohexylamine MS (ion spray) 5-yl)cyclohexyl]-N-cyclohexylacetamide456.3 (M + 1) 2112-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 39Cycloheptyl- MS (ion spray) 5-yl)cyclohexyl]-N-cycloheptylacetamideamine 470.2 (M + 1) 2122-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 39N-methyl,N- MS (ion spray)5-yl)cyclohexyl]-N-cyclohexyl-N-methylacetamide cyclohexyl- 470.02(M + 1) amine 2132-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 392-aminoindane MS (ion spray) 5-yl)-cyclohexyl]-N-indan-2-yl-acetamide490.2 (M + 1) 2142-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 391-naphthylamine MS (ion spray)5-yl)cyclohexyl]-N-naphthalen-1-yl-acetamide 500.2 (M+) 2159-Chloro-3-methyl-5-[3-(2-oxo-2-piperidin-1-yl-ethyl)- prep 39Piperidine MS (ion spray) cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one442.2 (M + 1) 216 N,N-Dibenzyl-2-[3-(9-chloro-3-methyl-4-oxo-5H- prep 39Dibenzylamine MS (ion spray)isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamide 554.3 (M + 1) 217N-Benzyl-2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 39N-benzyl,N- MS (ion spray) c]-quinolin-5-yl)cyclohexyl]-N-(3,4,5-(3,4,5-trimethy- 644.3 (M + 1) trimethoxybenzyl)acetamide oxy-benzyl)amine 2182-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 392-aminopyridine MS (ion spray) 5-yl)cyclohexyl]-N-pyridin-2-ylacetamide451.1 (M + 1) 2192-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 393-aminopyridine MS (ion spray) 5-yl)cyclohexyl]-N-pyridin-3-ylacetamide451.1 (M + 1) 2202-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 394-aminopyridine MS (ion spray) 5-yl)cyclohexyl]-N-pyridin-4-ylacetamide451.1 (M + 1) 221N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- cyclohexane-prep 44 MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-3-cyclohexylpropanamide propionic acid484.2 (M + 1) 222N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2-pyrazine- prep44 MS (ion spray) c]quinolin-5-yl)cyclohexylmethyl]pyrazin-2-ylcarboxamide carboxylic acid 452.1 (M + 1) 223N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2-thiophene-prep 44 MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-2-thiophen-2-ylacetamide acetic acid470.1 (M + 1) 224N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- 1-methyl-4-prep 44 MS (ion spray)quinolin-5-yl)cyclohexylmethyl]-2-(1-methyl-1H-imidazol-4-imidazoleacetic 468.1 (M + 1) yl)-acetamide acid HCl 225N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 4-phenoxy- prep44 MS (ion spray) c]quinolin-5-yl)cyclohexylmethyl]-4-phenoxy-benzamidebenzoic acid 541.8 (M+) 2264-Benzolyl-N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H- 4-benzoyl- prep 44MS (ion spray) isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamidebenzoic acid 554.2 (M+) 227 6-Fluoropyridine-2-carboxylic acid[3-(9-chloro-3-methyl-4- prep 1 Ex 632 MS (ion spray)oxo-5H-isoxazolo[4,3-c]quinolin-5- 469 (M⁺) yl)cyclohexylmethyl]amide228 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-D-(−)-mandelic Ex 634 MS (ion spray) flash chrom.5-yl)cyclohexyl]-2-(4-fluorophenyl)-2-hydroxyacetamide acid 484 (M⁺)(silica gel: 0-0.5% MeOH/ chloroform)gave both isomers 229Cis-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- 4-fluoro- Ex 632MS (ion spray) quinolin-5-yl))cyclohexyl]methyl}(5-fluoro(2-pyridyl))-picolinic acid 469 (M⁺). carboxamide 230Cis-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 6-methoxy- Ex 632MS (ion spray) c]quinolin-5-yl))cyclohexyl]methyl}(6-methoxy(2-pyridine-2- 481 (M⁺). pyridyl))carboxamide carboxylic acid 231Cis-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 3 Ex 632 MS(ion spray) c]quinolin-5-yl)cyclohexylmethyl]-5-methoxynicotinamide 481(M⁺). 232 cis-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-(d/l)-2,3- Ex 634 MS (ion spray) flash chrom.quinolin-5-yl)cyclohexyl]-2-(2,3-difluorophenyl)-2- difluoromandelic 502(M⁺). (silica gel: hydroxyacetamide acid 0-0.5% MeOH/ chloroform)gaveboth isomers 234 cis-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-(d/l)-3,4- Ex 634 MS (ion spray) flash chrom.c]quinolin-5-yl)-cyclohexyl]-2-(3,4-difluorophenyl)-2- difluoromandelic502 (M⁺). (silica gel: hydroxyacetamide acid 0-0.5% MeOH/chloroform)gave both isomers 235 cis{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- N-(t-butoxy- Ex 634MS(ES): (M + silica gel c]quinolin-5- carbonyl)-D- Na)⁺ 587.1 m/z,column eluted yl)cyclohexylcarbamoyl]phenylmethyl}carbamic acid t-butylphenyl-glycine (M-BOC)⁺ with 30% ester 465.1 m/z ethylacetate/ hexanes:isomer 1 R_(t) = 33.67 min. isomer 2: R_(t) = 23.81 min. Chiracel AD.236 N-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- trimethyl-acetic Ex633 MS(ES): c]quinolin-5-yl)cyclohexylcarbamoyl]phenylmethyl}-2,2- acid(M + 1)⁺ 549.1, dimethyl-propionamide 551.1 m/z. 237N-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- nicotinic acid Ex 633MS(ES): c]quinolin-5- (M + 1)⁺ 570.0,yl)cyclohexylcarbamoyl]phenylmethyl}nicotinamide 572.0 m/z 238Pyridine-2-carboxylic acid {[3-(9-chloro-3-methyl-4-oxo-5H- picolinicacid Ex 633 MS(ES): isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-(M + 1)⁺ 570.2, phenylmethyl}amide 572.3 m/z 239N-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- isonicotinic Ex 633MS(ES): c]quinolin-5- acid (M + 1)⁺ 570.3,yl)cyclohexylcarbamoyl]phenylmethyl}isonicotinamide 572.3 m/z 2402-t-Butylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H- prep 11 Ex 634 MS(ES):Isomer 1 isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2- (M + 1)⁺ 521.2,38% phenylacetamide 522.2, 523.2 m/z 2412-t-Butylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H- prep 11 Ex 634 MS(ES):Isomer 2 isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2- (M + 1)⁺ 521.2,30% phenylacetamide 522.2, 523.2 m/z 242N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 13 Ex634 MS(ES): Isomer 1 5-yl)cyclohexyl]-2-(2,2-dimethylpropylamino)-2-(M + 1)⁺ 535.3, 29% phenylacetamide 536.3, 537.3 m/z. 243N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 13 Ex634 MS(ES): Isomer 2 5-yl)cyclohexyl]-2-(2,2-dimethylpropylamino)-2-(M + 1)⁺ 535.3, 44% phenylacetamide 536.3, 537.3 m/z. 244N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- nicotinicacid- Ex 619 MS (ion spray) 5-yl)cyclohexylmethyl]-1-oxynicotinamideN-oxide 467.2 (M+). 2456-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 4-amino- Ex 619MS (ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamide nicotinicacid 466.3 (M+). 246N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-3-pyridylacetic Ex 619 MS (ion spray)5-yl)-cyclohexylmethyl]-2-pyridin-3-yl-acetamide acid HCl 465.0 (M+).247 Quinoline-3-carboxylic acid [3-(9-chloro-3-methyl-4-oxo-3-quinoline- Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]amide carboxylic acid501 (M+). 248 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-6-(1H-pyrazol- Ex 619 MS (ion spray)5-yl)-cyclohexylmethyl]-6-pyrazol-1-yl-nicotinamide 1-yl)-nicotinic517.2 (M+). acid 249N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-3-pyridylpropionic Ex 619 MS (ion spray)5-yl)-cyclohexylmethyl]-3-pyridin-3-yl-propionamide acid 479.1 (M+). 250N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- 6-trifluoro-Ex 619 MS (ion spray)5-yl)-cyclohexylmethyl]-6-trifluoromethyl-nicotinamide methylnicotinic501 (M+). acid 2515-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 5- Ex 619 MS(ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamideaminonicotinic 466.2 (M+). acid 252 Pyrimidine-5-carboxylic acid[3-(9-chloro-3-methyl-4-oxo- prep 15 Ex 619 MS (ion spray)5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-amide 452.2 (M+).253 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-4-(methyl- Ex 619 MS (ion spray)5-yl)-cyclohexylmethyl]-4-methylaminobenzamide amino)benzoic 479.0 (M+).acid 254 6-Methyl-pyridine-2-carboxylic acid [3-(9-chloro-3-methyl-6-methyl- Ex 619 MS (ion spray) 4-oxo-5H-isoxazolo[4,3-c]quinolin-5-picolinic acid 465.0 (M+). yl)cyclohexylmethyl]amide 2554-Chloro-pyridine-2-carboxylic acid [3-(9-chloro-3-methyl-4- 4-chloro-Ex 619 MS (ion spray) oxo-5H-isoxazolo[4,3-c]quinolin-5- picolinic acid486.9 (M+). yl)cyclohexylmethyl]amide (TCI-US) 2562,6-Dichloro-N-[3-(9-chloro-3-methyl-4-oxo-5H- 2,6-dichloro- Ex 619 MS(ion spray) isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-isonicotinic 518.9 (M+). isonicotinamide acid 257N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- 2-fluoro- Ex619 MS (ion spray) 5-yl)-cyclohexylmethyl]-2-fluoroisonicotinamideisonicotinic 469.0 (M+). acid 258 Furo[3,2-b]pyridine-5-carboxylic acid[3-(9-chloro-3-methyl- Furo[3,2-b]- Ex 619 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]- pyridine-5-491.2 (M+). amide carboxylic acid 259 6-Chloro-pyridine-2-carboxylicacid [3-(9-chloro-3-methyl-4- 6-chloro-2- Ex 619 MS (ion spray)oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-pyridinecarboxylic 485.2 (M+). amide acid (SALOR) 2606-Methoxy-pyridine-2-carboxylic acid [3-(9-chloro-3-methyl- prep 16 Ex619 MS (ion spray) 4-oxo-5H-isoxazolo[4,3-c]quinolin-5- 481.1 (M+).yl)cyclohexylmethyl]amide 261 4-Methoxypyridine-2-carboxylic acid[3-(9-chloro-3-methyl- 4-methoxy- Ex 619 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]quinolin-5- picolinic acid 481.2 (M+).yl)cyclohexylmethyl]amide HCl 2625,6-Dichloro-N-[3-(9-chloro-3-methyl-4-oxo-5H- 5,6-dichloro- Ex 619 MS(ion spray) isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]- nicotinicacid 519.0 (M+). nicotinamide 2632-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2-chloro-6- Ex619 MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-6-methylisonicotinamidemethylpyridine- 498.8, 500.87 4-carboxylic (M+). acid 264N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- 5-methyl- Ex619 MS (ion spray) 5-yl)-cyclohexylmethyl]-5-methyl-nicotinamidenicotinic acid 465.1 (M+). 265N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 19 Ex619 MS (ion spray) 5-yl)-cyclohexylmethyl]-6-methoxy-nicotinamide 481.0(M+). 266 5-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-5-chloro- Ex 619 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamide nicotinic acid 485.0(M+). 267 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-phenylacetic Ex 619 MS (ion spray)5-yl)-cyclohexylmethyl]-2-phenylacetamide acid 501 (M+). 2684-Fluoronaphthalene-1-carboxylic acid [3-(9-chloro-3- 4-fluoro-1- Ex 619MS (ion spray) methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- naphthoicacid 518.1 (M+). yl)cyclohexylmethyl]-amide 269N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- 2-methyl-3-Ex 619 MS (ion spray)5-yl)-cyclohexylmethyl]-3-hydroxy-2-methylbenzamide hydroxy- 479.9 (M+).benzoic acid 270N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (S)-(+)-α- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-methoxy-2-phenylacetamidemethoxyphenyl 480.1 (M+). acetic acid 271N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (R)-(−)-α- Ex634 MS (ion spray) 5-yl)cyclohexyl]-2-methoxy-2-phenylacetamidemethoxyphenyl 480.1 (M+). acetic acid 272N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-(S)-(−)-α-methoxy- Ex 634 MS (ion spray)5-yl)cyclohexyl]-3,3,3-trifluoro-2-methoxy-2-phenyl- α- 548.1 (M+).propionamide (trifluoromethyl) phenylacetic acid 273 Acetic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- (R)-(−)-O- Ex 634 MS (ionspray) c]quinolin-5-yl)cyclohexylcarbamoyl]phenylmethyl ester acetyl-508.1 (M+). mandelic acid 274 Acetic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- (S)-(+)-O- Ex 634 MS (ionspray) c]quinolin-5-yl)cyclohexylcarbamoyl]phenylmethyl ester acetyl-508.1 (M+). mandelic acid 275N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- phenoxy- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-phenoxy-2-phenylacetamidephenylacetic acid 542.1 (M+). 276{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- CBZ-D(−)- Ex634 MS (ion spray) 5-yl)cyclohexylcarbamoyl]phenylmethyl}carbamic acidphenylglycine 599.2 (M+). benzyl ester 277{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Z-Phg-OH Ex634 MS (ion spray) 5-yl)cyclohexylcarbamoyl]phenylmethyl}carbamic acid599.2 (M+) benzyl ester 278N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Morpholin-4-Ex 634 MS (ion spray)5-yl)cyclohexyl]-2-morpholin-4-yl-2-phenylacetamide yl-phenylacetic535.2 (M+) acid 2792-(Acetyl-methyl-amino)-N-[3-(9-chloro-3-methyl-4-oxo-5H- (acetylmethyl-Ex 634 MS (ion spray) isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-amino)phenyl- 521.2 (M+) phenylacetamide acetic acid 280N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- phenylphenyl-Ex 634 MS (ion spray) 5-yl)cyclohexyl]-2-phenyl-2-phenylaminoacetamideaminoacetic 541.1 (M+) acid 281N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-dimethylamino- Ex 634 MS (ion spray) diastereomers5-yl)-cyclohexyl]-2-dimethylamino-2-phenyl-acetamide phenylacetic 493.0(M+) were acid separated 282N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- phenylthio-Ex 634 MS (ion spray)5-yl)cyclohexyl]-2-phenyl-2-thiomorpholin-4-ylacetamide morpholin-4-550.9 (M+) ylacetic acid 283N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (4-methyl- Ex634 MS (ion spray) 5-yl)cyclohexyl]-2-(4-methylpiperazin-1-yl)-2-piperazin-1- 548.2 (M+) phenylacetamide yl)phenyl- acetic acid 2842-(4-Acetylpiperazin-1-yl)-N-[3-(9-chloro-3-methyl-4-oxo-(4-acetyl-piperazin- Ex 634 MS (ion spray)5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenyl- 1-yl)- 576.2 (M+)acetamide phenylacetic acid 285N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (indan-2-yl-Ex 634 MS (ion spray) diastereomers5-yl)cyclohexyl]-2-(indan-2-ylamino)-2-phenylacetamide amino)- 581.0(M+) were phenylacetic separated acid 286N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (S)-(+)-2- Ex634 MS (ion spray) 5-yl)cyclohexyl]-2-hydroxy-2-phenylpropionamidehydroxy-2- 480.13 (M+) phenylpropionic acid 287N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (R)-(−)-2- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-propionamidehydroxy-2- 480.1 (M+) phenylpropionic acid 288N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- m-methoxy- Ex634 MS (ion spray) diastereomers5-yl)cyclohexyl]-2-hydroxy-2-(3-methoxyphenyl)acetamide mandelic acid496.1 (M+) were separated 289N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- p-methoxy- Ex634 MS (ion spray) diastereomers5-yl)cyclohexyl]-2-hydroxy-2-(4-methoxyphenyl)acetamide mandelic acid496.1 (M+) were separated 290N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- p-trifluoro-Ex 634 MS (ion spray) diastereomers5-yl)cyclohexyl]-2-hydroxy-2-(4-trifluoromethylphenyl)- methylmandelic534.0 (M+) were acetamide acid separated 291N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- D-3-phenyl-Ex 634 MS (ion spray) 5-yl)cyclohexyl]-2-hydroxy-3-phenylpropionamidelactic acid 480.2 (M+) 292N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- L-3-phenyl-Ex 634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-3-phenyl-propionamidelactic acid 480.0 (M+) 293N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- DL-tropicacid Ex 634 MS (ion spray) diastereomers5-yl)-cyclohexyl]-3-hydroxy-2-phenyl-propionamide 480.1 (M+). wereseparated 294 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-(R)-(−)-3- Ex 634 MS (ion spray)5-yl)-cyclohexyl]-2-(3-chloro-phenyl)-2-hydroxyacetamide chloro- 500.1(M+) mandelic acid 295N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- racemic 3- Ex634 MS (ion spray) diastereomers5-yl)-cyclohexyl]-2-(3-chloro-phenyl)-2-hydroxyacetamide chloromandelic500.1 (M+) were acid separated by radial HPLC 296N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- hydroxy-m- Ex634 MS (ion spray) diastereomers5-yl)-cyclohexyl]-2-hydroxy-2-m-tolylacetamide tolylacetic acid 480.0(M+) were separated 297N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (2-Fluoro- Ex634 MS (ion spray) diastereomers5-yl)-cyclohexyl]-2-(2-fluoro-phenyl)-2-hydroxyacetamide phenyl)- 480.0(M+) were hydroxy-acetic separated acid 298N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- benzylic acidEx 634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-2,2-diphenylacetamide542 (M+) 299 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-dimethylphenyl Ex 634 MS (ion spray)5-yl)cyclohexyl]-2-phenylisobutyramide acetic acid 478.1 (M+) 3001-Phenylcyclopropanecarboxylic acid [3-(9-chloro-3-methyl- 1-phenyl-1-Ex 634 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amide cyclopropyl-476.1 (M+) acetic acid 301N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- α-fluoro- Ex634 MS (ion spray) 5-yl)cyclohexyl]-2-fluoro-2-phenylacetamidephenylacetic 468.1 (M+) acid 302N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-difluorophenyl- Ex 634 MS (ion spray)5-yl)cyclohexyl]-2,2-difluoro-2-phenylacetamide acetic acid 486.1 (M+)303 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-phenylphenylth Ex 634 MS (ion spray)5-yl)-cyclohexyl]-2-phenyl-2-phenylsulfanyl-acetamide ioacetic acid558.0 (M+). (Lancaster) 304N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (R)-(−)-2- Ex634 (ion spray) 5-yl)-cyclohexyl]-2-phenyl-propionamide phenyl- 464.2(M+) propionic acid 305N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (S)-(+)-2- Ex634 MS (ion spray) 5-yl)cyclohexyl]-2-phenylpropionamide phenylpropionic464.2 (M+) acid 306 1-Phenylcyclohexanecarboxylic acid[3-(9-chloro-3-methyl- 1-phenyl-1- Ex 634 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amide cyclohexane518.2 (M+) carboxylic acid (Acros) 307N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- α-S-methyl-Ex 634 MS (ion spray)5-yl)cyclohexyl]-2-methylsulfanyl-2-phenylacetamide phenylacetic 495.9(M+) acid 308 Bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid[3-(9- 1-benzocyclo- Ex 634 MS (ion spray)chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-butenecarboxylic 461.9 (M+) cyclohexyl]amide acid 309{2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- N-BOC-2- Ex 634 MS (ionspray) c]quinolin-5-yl)cyclohexylcarbamoyl]indan-2-yl}carbamicaminoindane-2- 491 (M-BOC) acid t-butyl ester carboxylic acid 3103-Oxo-indan-1-carboxylic acid [3-(9-chloro-3-methyl-4-oxo- 3-oxo-1- Ex634 MS (ion spray) 5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amideindancarboxylic 489.9 (M+) acid 3113-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- N-t-BOC-L- Ex634 MS (ion spray)yl)-cyclohexylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-1,2,3,4-tetrahydro- 591.2 (M+) carboxylic acid t-butyl esterisoquinoline-3- carboxylic acid (Sigma) 3123-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- N-t-BOC-D- Ex634 MS (ion spray)yl)-cyclohexylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2- 1,2,3,4- 591.3(M+) carboxylic acid t-butyl ester tetrahydro- isoquinoline-3-carboxylic acid (BAChem) 313N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-6-fluoronicotinic Ex 634 MS (ion spray)5-yl)-cyclohexyl]-6-fluoronicotinamide acid 455.0 (M+) 3143-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-BOC-azetidine- Ex 634 MS (ion spray)5-yl)cyclohexylcarbamoyl]-azetidine-1-carboxylic acid t- 3-carboxylic415.08 butyl ester acid (M +− BOC). 3152-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- N-t-BOC-D- Ex634 MS (ion spray) 5-yl)cyclohexylcarbamoyl]pyrrolidine-1-carboxylicacid t- proline 529.2 (M+). butyl ester 316N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (S)-(+)-2- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-3,3-dimethyl-butyramidehydroxy-3,3- 446.2 (M+) dimethylbutyric acid 317N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (L)-(+)- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-cyclohexyl-2-hydroxyacetamidehexahydro- 472.2 (M+) mandelic acid 318N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (R)-(−)- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-cyclohexyl-2-hydroxyacetamidehexahydro- 472.2 (M+) mandelic acid 319N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-3,3,3-trifluoro- Ex 634 MS (ion spray) diastereomers5-yl)-cyclohexyl]-3,3,3-trifluoro-2-hydroxy-propionamide lactic acid480.0 (M+) were separated 320N-[3-9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- 2-methyllacticEx 634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-2-methyl-propionamideacid 417.9 (M+) 321 [1-({[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-N-t-butyl-α- Ex 638 MS(ES)c]quinolin-5-yl)-cyclohexyl-carbamoyl]-phenylmethyl}- aminoisobutryic[M + H]⁺ = carbamoyl)-1-methylethyl]-carbamic acid t-butyl ester acid650.2 m/z 322 Pyridine-2-carboxylic acid{[3-(9-chloro-3-methyl-4-oxo-5H- pyridine-2- Ex 638 MS(ES)isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl- carboxylicacid [M + H]⁺ = methyl}-amide 570.2 m/z 323 Pyridine-3-carboxylic acid{[3-(9-chloro-3-methyl-4-oxo-5H- pyridine-3- Ex 638 MS(ES)isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl- carboxylicacid [M + H]⁺ = methyl}-amide 570.2 m/z 324 Pyridine-4-carboxylic acid{[3-(9-chloro-3-methyl-4-oxo-5H- pyridine-4- Ex 638 MS(ES)isoxazolo[4,3-c-]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl- carboxylicacid [M + H]⁺ = methyl}-amide 570.2 m/z 325N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- 2-Methyl-2-Ex 634 MS(ES) exact5-yl)-cyclohexyl]-2-[1,2,4]triazol-1-yl-isobutyramide [1,2,4]triazol-mass calc'd: 1-yl-propionic [M + H]⁺ = acid 469.1755 m/z. 326{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- t- Ex 634MS(ES) calc'd: 5-yl)-cyclohexylcarbamoyl]-pyridin-3-yl-methyl}-carbamicbutoxycarbon- [M + H]⁺ = acid t-butyl ester ylaminopyridin- 565.20 m/z;3-ylacetic acid [M + Na]⁺ = 588.20 m/z. 327N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- glycolic acidEx 634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-acetamide 389.9 (M+)racemic cis 328N-(3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- D-alpha- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-3-methyl-butyramidehydroxyisovaleric 431.9 (M+) acid racemic cis 329N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-(S)-3-hydroxy- Ex 634 MS (ion spray)5-yl)-cyclohexyl]-3-hydroxy-3-phenyl-propionamide 3- 480.1 (M+)phenylpropionic racemic cis acid 330N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-(R)-3-hydroxy- Ex 634 MS (ion spray)5-yl)-cyclohexyl]-3-hydroxy-3-phenyl-propionamide 3-phenyl- 480.1 (M+)propionic acid racemic cis 331N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (S)-(+)-2- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-3-methylbutyramidehydroxy-3- 431.9 (M+) methylbutryric racemic cis acid 3321-Hydroxy-cyclopropanecarboxylic acid [3-(9-chloro-3- 1-hydroxy-1- Ex634 MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-cyclopropane- 416.0 (M+) amide carboxylic acid racemic cis 333{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- N-t-BOC- Ex634 MS (ion spray) 5-yl)-cyclohexylcarbamoyl]-methyl}-methyl-carbamicacid t- sarcosine 503.2 (M+) butyl ester racemic cis 334N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- N,N-dimethyl-Ex 634 MS (ion spray) 5-yl)-cyclohexyl]-2-dimethylamino-acetamideglycine 416.9 (M+) racemic cis 335{1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- N-t-BOC-α- Ex 634 MS(ion spray) c]quinolin-5-yl)-cyclohexylcarbamoyl]-1-methyl-ethyl}-aminoisobutyric 516.9 (M+) carbamic acid t-butyl ester acid racemic cis336 {[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-N-t-butoxycarbonyl- Ex 634 MS (ion spray)5-yl)-cyclohexylcarbamoyl]-methyl}-carbamic acid t-butyl glycine 489.1(M+) ester racemic cis 337 2-Hydroxy-hexanoic acid[3-(9-chloro-3-methyl-4-oxo-5H- 2-hydroxy- Ex 634 MS (ion spray)diastereomers isoxazolo[4,3-c]quinolin-5yl)-cyclohexyl]-amide caproicacid 446.2 (M+) were racemic cis separated 338N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- salicylicacid Ex 634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxybenzamide 452.0(M+) racemic cis 339 4-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-prep 285 Ex 634 MS (ion spray)c)quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}- 633.9 (M+)piperazine-1-carboxylic acid t-butyl ester racemic cis 340{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- BOC-N-Me- Ex634 MS (ion spray) 5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-methyl-Phg-OH 578.9 (M+) carbamic acid t-butyl ester racemic cis 341N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 287 Ex634 MS (ion spray) diastereomers5-yl)-cyclohexyl]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2- 578.1 (M+)were phenyl-acetamide racemic cis separated 342N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 288 Ex634 MS (ion spray) diastereomers5-yl)-cyclohexyl]-2-phenyl-2-(4-pyridin-2-yl-piperazin-1-yl)- 610.9 (M+)were acetamide racemic cis separated 343N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 290 Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-piperidin-1-yl-acetamide 457.1(M+) racemic cis 344N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 292 Ex634 MS (ion spray)5-yl)-cyclohexyl]-2-(4-methyl-piperazin-1-yl)-acetamide 472.0 (M+)racemic cis 345N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- N,N-diethyl-Ex 634 MS (ion spray) 5-yl)-cyclohexyl]-2-diethylamino-acetamide glycinesodium 445.0 (M+) salt 346N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 293 Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-(methyl-phenyl-amino)-acetamide479.0 (M+) racemic cis 347N-[3-(9-Chloro-3-methyl-4-oxa-5H-isoxazolo[4,3-c]quinolin- prep 294 Ex634 MS (ion spray)5-yl)-cyclohexyl]-2-phenyl-2-(pyridin-3-yloxy)-acetamide 543.0 (M+) 348N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 296 Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-(pyridin-3-yloxy)-acetamide 467.1(M+) 349 {1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 297 Ex634 MS (ion spray)c]quinolin-5-yl)-cyclohexylcarbamoyl]-cyclohexyl}carbamic 557.2 (M+)acid t-butyl ester 350N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 299 Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-morpholin-4-yl-acetamide 459.0(M+) 351 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep301 Ex 634 MS (ion spray)5-yl)-cyclohexyl]-2-(4-hydroxy-piperidin-1-yl)-acetamide 473.1 (M+) 352N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 303 Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-(2-oxo-2H-pyridin-1-yl)-acetamide467.1 (M+) 353N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 304 Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-(pyridin-4-yloxy)-acetamide 467.0(M+) 354 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-(4-pyridylthio)- Ex 634 MS (ion spray)5-yl)-cyclohexyl]-2-(pyridin-4-ylsulfanyl)-acetamide acetic acid 483.1(M+) 355 {[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-N-t-BOC-D-α- Ex 634 MS (ion spray)5-yl)-cyclohexylcarbamoyl]-cyclohexyl-methyl}-carbamic cyclohexyl- 571.2(M+) acid t-butyl ester glycine 356{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- N-t-BOC-L-α-Ex 634 MS (ion spray)5-yl)-cyclohexylcarbamoyl]-cyclohexyl-methyl}-carbamic cyclohexyl- 571.2(M+) acid t-butyl ester glycine 357 Thieno[3,2-b]pyridine-2-carboxylicacid [3-(9-chloro-3- thieno[3,2-b]- Ex 634 MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]- pyridine-2-493.0 (M+). amide carboxylic acid 358N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-thieno[3,2-b]- Ex 634 MS (ion spray)5-yl)-cyclohexyl]-2-(2-chloro-pyridin-4-yloxy)-acetamide pyridine-2-501.0 (M+) carboxylic acid 359N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (quinolin-3-Ex 634 MS (ion spray) 5-yl)-cyclohexyl]-2-(quinolin-3-yloxy)-acetamideyloxy)acetic 517.2 (M+) acid HCl (SALOR) 3602-t-Butylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H- prep 305 Ex 634 MS (ionspray) isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-acetamide 445.1 (M+)361 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-(pyridin-2- Ex 634 MS (ion spray)5-yl)-cyclohexyl]-2-(pyridin-2-ylsulfanyl)-acetamide ylsulfanyl)acetic483.1 (M+) acid (Maybridge) 362N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- trans-3-(3-Ex 634 MS (ion spray) 5-yl)-cyclohexyl]-3-pyridin-3-yl-acrylamidepyridyl)acryl-ic 463.1 (M+) acid 363N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- trans-3- Ex634 MS (ion spray) 5-yl)-cyclohexyl]-3-pyridin-2-yl-acrylamidePyridin-2-yl- 463.1 (M+) acrylic acid 364N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- trans-3-(4-Ex 634 MS (ion spray) 5-yl)-cyclohexyl]-3-pyridin-4-yl-acrylamidepyridyl)acrylic 463.0 (M+) acid 365{1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- N-t-BOC-L- Ex 634 MS(ion spray) c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-hydroxy-ethyl}-Serine 519.0 (M+) carbamic acid t-butyl ester 366{1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- N-t-BOC-D- Ex 634 MS(ion spray) c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-hydroxy-ethyl}-Serine 519.0 (M+) carbamic acid t-butyl ester 367N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 306 Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-(6-methoxy-pyridin-3-ylamino)-496.2 (M+) acetamide 368N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 307 Ex634 MS (ion spray) 5-yl)-cyclohexyl]-2-(pyridin-3-yloxy)-propionamide481.2 (M+) 369N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- (pyridin-2-Ex 634 MS (ion spray) 5-yl)-cyclohexyl]-2-(pyridin-2-yloxy)-acetamideyloxy) acetic 467.0 (M+) acid 370{1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- N-BOC-L- Ex 634 MS (ionspray) c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-phenyl-ethyl}-phenyl-alanine 579.2 (M+) carbamic acid t-butyl ester 371N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- benzylic acidEx 634 MS (ion spray) 5-yl)-cyclohexyl]-2-hydroxy-2,2-diphenyl-acetamide542 (M+) 372 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-9-hydroxy-9- Ex 634 MS (ion spray)5-yl)-cyclohexyl]-2-(9H-fluoren-9-yl)-2-hydroxy-acetamide fluorene-540.1 (M+) carboxylic acid 373N-[3R-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 6-fluoro- prep 137MS(ES+) c]quinolin-5-yl)R-cycloheptylmethyl]-6-fluoro-nicotinamidenicotinic acid m/z = 483.1 3742-(Benzenesulfonyl-pyridin-2-yl-amino)-N-[3-(9-chloro-3-(benzenesulfonyl- prep 137 MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl}- pyridin-2-606.1 (M+) acetamide yl-amino) acetic acid (Bionet) 3752-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 3552-chloro-6- MS (ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-6-methoxy-meth-oxy- 514.8 (M+) isonicotinamide pyridine-4- carboxylic acid 3761-Methyl-piperidine-3-carboxylic acid [3-(9-chloro-3-methyl- prep 355prep 357 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]- 471.2 (M+)amide 377 3-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 355 prep358 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-carbamoyl}-piperidine-1- 557.2 (M+)carboxylic acid tert-butyl ester 378N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 691-methyl-3- MS (ion spray)5-yl)-cyclohexyl]-2-(1-methyl-1H-indol-3-yl)-acetamide indoleacetic503.3 (M+) acid 379 2-(Pyridin-3-yloxy)-hexanoic acid[3-(9-chloro-3-methyl-4- prep 362 prep 357 MS (ion spray)oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide 523.3 (M+) 380N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin- prep 380R-Madelic acid MS (ES+) m/z5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-acetamide 466.1 (M+H)⁺, (ES-) 464.2(M − H)⁻, 381 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-prep 380 3-Fluoro- MS (ES+) m/z5-yl)-cyclohexyl]-2-(3-fluorophenyl)acetamide phenylacetic 468.1 (M +H)⁺, acid (ES-) 466.2 (M − H)⁻ 382N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- phenylbutyricPrep 44 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-4-phenyl-butanamide acid 492.2 (M+)383 N-[(1S,3R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3-benzoyl-Prep 44 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-4-oxo-4-phenyl- propionic acid 506.2(M+) butanamide 384N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3-(4-hydroxy-Prep 44 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-3-(4-hydroxy-phenyl)-phenyl)propionic 494.2 (M + 1) propanamide acid 385N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3-indole- Prep44 MS (ion spray) c]-quinolin-5-yl)cyclohexylmethyl]-3-(1H-indol-3-yl)-propionic acid 516.9 (M+) propanamide 386N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- N,N-dimethyl-Prep 44 MS (ion spray)c]-quinolin-5-yl)-cyclohexylmethyl]-2-dimethylamino- glycine HCL 431.2(M + 1) acetamide 387 (2R)-N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-(D)-BOC- Prep 44 MS (ion spray)isoxazolo[4,3-c]quinolin-5-yl)Cyclohexylmethyl]-2-[t- benzyloxyserine523.2 (M − 100 butoxycarbonyl-amino]-3-(phenylmethoxy)propanamide(M-BOC) 388 (2S)-N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H- (L)-BOC- Prep44 MS (ion spray) isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-2-[t-benzyloxyserine 523.0 (M − 100butoxycarbonyl-amino]-3-(phenylmethoxy)propanamide (M-BOC) 3892-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep 47cyclohexylamine MS (ion spray)c]quinolin-5-yl)-cyclohexyl]-N-cyclohexyl-acetamide 456.2 (M + 1) 3902-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep 47 anilineMS (ion spray) c]quinolin-5-yl)-cyclohexyl]-N-phenyl-acetamide 448.1(M + 1) 391 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep47 2-aminopyridine MS (ion spray)c]quinolin-5-yl)-cyclohexyl]-N-pyridin-2-yl-acetamide 451.2 (M + 1) 3922-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep 473-aminoaceto- MS (ion spray)c]quinolin-5-yl)-cyclohexyl]-N-(3-acetyl-phenyl)acetamide phenone 492.2(M + 1) 393 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep47 3-methanesulfonyl- MS (ion spray)c]-quinolin-5-yl)cyclohexyl]-N-(3-methanesulfonylphenyl)- aniline HCl528.2 (M+) acetamide 3942-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep 474-fluoroaniline MS (ion spray)c]quinolin-5-yl)cyclohexyl]-N-(4-fluoro-phenyl)-acetamide 468.2 (M + 1)395 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep 473-fluoroaniline MS (ion spray)c]quinolin-5-yl)cyclohexyl]-N-(3-fluoro-phenyl)-acetamide 468.2 (M + 1)396 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep 47 3-MS (ion spray) c]quinolin-5-yl)cyclohexyl]-N-(3-methoxy-phenyl)-methoxyaniline 480.2 (M + 1) acetamide 397N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- (3,5- Prep 48 MS(ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-3,5-dimethoxy-4-methyl-dimethoxy-4- 524.3 (M + 1) benzamide methyl)- benzoic acid 398N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 1-methyl- Prep48 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-1-methylpiperid-4-yl piperidine-4-471.2 (M + 1) carboxamide carboxylic acid HCl 399N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 1,2,3- Prep 48MS (ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-[1,2,3]thiadiazol-4-ylthiadiazole-4- 458.1 (M + 1) carboxamide carboxylic acid 4006-Chloro,-N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H- 6- Prep 48 MS (ionspray) isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]- chloronicotinic485.1 (M+) nicotinamide acid 4016-Methyl-N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H- 6-methyl- Prep 48 MS(ion spray) isoxazolo-[4,3-c]quinolin-5-yl)cyclohexylmethyl]- nicotinicacid 465.1 (M + 1) nicotinamide 4022-Methyl-N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H- 2- Prep 48 MS (ionspray) isoxazolo-[4,3-c]quinolin-5- methylnicotinic 465.1 (M + 1)yl)cyclohexylmethyl]nicotinamide acid 4032-Fluoro-N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H- 2- Prep 48 MS (ionspray) isoxazolo-[4,3-c]quinolin-5- fluoronicotinic 469.1 (M + 1)yl)cyclohexylmethyl]nicotinamide acid. 404N-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 5- Prep 48 MS(ion spray) c]quinolin-5-yl)cyclohexylmethyl)-5-fluoro-nicotinamidefluoronicotinic 469.1 (M + 1) acid 405N-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 2-(methylthio)-Prep 48 MS (ion spray)c]-quinolin-5-yl)cyclohexylmethyl]-2-methylsulfanyl- nicotinic acid497.0 (M+) nicotinamide 4062-Chloro-N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H- 2-chloroisonicotinicEx 615 MS (ion spray)isoxazolo-[4,3-c]quinolin-5-yl)cyclohexylmethyl]isonicotine acid 485.1,487.1 (M+) 407 N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-pyrazinecarboxylic Ex 615 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-pyrazin-2-yl acid 452.1 (M + 1)carboxamide 408 N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-cinnoline-4- Ex 615 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-cinnolin-4-yl carboxylic acid 502.2(M + 1) carboxamide 409N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- M-methyl- Ex 615MS (ion spray) c]quinolin-5-yl)cyclohexylmethyl]-1-methyl-1H-pyrrol-3-ylpyrrole-2- 453.2 (M + 1) carboxamide carboxylic acid 410N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 4-pyrazole- Ex615 MS (ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-1H-pyrazol-4-ylcarboxylic acid 440.1 (M + 1) carboxamide 411N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- indole-3- Ex 615MS (ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-1H-indol-3-ylcarboxylic acid 489.1 (M + 1) carboxamide 412N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- indole-2- Ex 615MS (ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-1H-indol-2-ylcarboxylic acid 488.1 (M+) carboxamide 413N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 1-methyl- Ex 615MS (ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-1-methyl-1H-indol-2-ylindole-2- 503.1 (M+) carboxamide carboxylic acid 414N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- indole-4- Ex 615MS (ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-1H-indol-4-ylcarboxylic acid 489.1 (M+) carboxamide 415N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 1-methyl-4- Ex615 MS (ion spray) c]-quinolin-5-yl)cyclohexylmethyl]-2-(1-methyl-1H-imidazole 468 (M⁺), 466 imidazol-4-yl)acetamide acetic acid (M⁻ − 1)hydrochloride 416 3-Benzoyl-N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H- 3-Ex 615 MS (ion spray)isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-benzamidebenzoylbenzoic 554 (M⁺), 552 acid (M⁻ − 1) 417N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3- Ex 615 MS(ion spray) c]quinolin-5-yl)-cyclohexylmethyl]-3-phenoxy-benzamidephenoxybenzoic 542 (M⁺), 540 acid (M⁻ − 1) 418N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 4-methoxy- Ex615 MS (ion spray)c]quinolin-5-yl)-cyclohexylmethyl]-4-methoxythiophen-3-yl thiophene-3-486 (M⁺), 484 carboxamide carboxylic acid (M⁻ − 1) 4191,2,5-Trimethyl-1H-pyrrole-3-carboxylic acid [(1R,3S)-3- 1,2,5- Ex 615MS (ion spray) (9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-trimethylpyrrole- 481 (M⁺) yl)-cyclohexylmethyl]-amide 3-carboxylic acid420 N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 6-Fluoro- Ex615 MS (ion spray)c]quinolin-5-yl)cyclohexylmethyl]-6-fluoronicotinamide nicotinic acid469 (M⁺) 421 2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-Prep 63 3,4,5,- MS (ion spray)5-yl)-2,2-dimethylcyclobutyl]-N-(3,4,5-trimethoxyphenyl)- trimethoxy 450(M⁺), 448 acetamide aniline (M⁻ − 1) 4222-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Prep 63aniline MS (ion spray) 5-yl)-2,2-dimethylcyclobutyl]-N-phenylacetamide540 (M⁺), 538 (M⁻ − 1) 4232-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Prep 633-aminopyridine MS (ion spray)5-yl)-2,2-dimethylcyclobutyl]-N-pyridin-3-ylacetamide 451 (M⁺), 449 (M⁻− 1) 424 N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- 3-fluorophenyl-Prep 68 MS (ion spray)c]quinolin-5-yl)cyclohexyl]-2-(3-fluorophenyl)acetamide acetic acid 468(M⁺), 466 (M⁻ − 1) 425 N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-3-fluorophenyl- prep 69 MS (ion spray)c]quinolin-5-yl)cyclohexyl]-2-(3-fluorophenyl)acetamide acetic acid 468(M⁺), 466 (M⁻ − 1) 426N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-3-pyridylacetic prep 69 MS (ion spray)5-yl)cyclohexyl]-2-pyridin-3-ylacetamide acid HCl 451 (M⁺), 449 (M⁻ − 1)427 N-[-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-4-pyridylacetic prep 69 MS (ion spray)5-yl)cyclohexyl]-2-pyridin-4-ylacetamide acid HCl 451 (M⁺), 449 (M⁻ − 1)428 N[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-1-methyl-4- prep 69 MS (ion spray)5-yl)cyclohexyl]-2-(1-methyl-3H-imidazol-4-yl)acetamide imidazoleacetic454 (M⁺), 452 acid HCl (M⁻ − 1) 4292-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-N-BOC-(S)-(−)- prep 69 MS (ion spray)5-yl)cyclohexylcarbamoyl]-2,3-dihydroindole-1-carboxylic indoline-2- 477(M⁺ − acid t-butyl ester carboxylic acid BOC + 1) 430[[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- N-BOC-L-4-prep 69 MS (ion spray)yl)cyclohexylcarbamoyl]-(4-fluorophenyl)methyl]carbamic fluorophenyl-483 (M⁺ − acid t-butyl ester glycine BOC + 1) 431N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-diphenylacetic prep 69 MS (ES) 526.25-yl)cyclohexyl]-2,2-diphenylacetamide acid m/z[M + H]⁺ 4322-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 943,4,5-trimethoxy MS (FIA) m/z = diastereomers5-yl]-N-3,4,5-trimethoxyphenylacetamide aniline 540.5 were separated 4333-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 102cyclobutylamine MS (ES+) (m/z) ylmethyl)-cyclohexanecarboxylic acidcyclobutylamide 428.1 [M + 1] 4343-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 102cyclohexylamine Mass Spectrum ylmethyl)-cyclohexanecarboxylic acidcyclohexylamide (FIA) (m/z) 456.3 [M + 1] 4353-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 102aniline MS (FIA) (m/z) ylmethyl)-cyclohexanecarboxylic acid phenylamide448.1 [M − 1] 4363-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 1023-aminopyridine Mass Spectrum ylmethyl)-cyclohexanecarboxylic acidpyridin-2-ylamide (FIA) (m/z) 451.1 [M + 1] 437N-(3,4,5-trimethoxyphenyl)[3-methyl-4-oxo-9-chloro-5H- prep 120trimethoxyaniline MS (ion spray) diastereomersisoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amide 526.2 (M + 1) wereseparated 438 2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-prep 145 aniline MS (ion spray) 5-yl)-cyclohexyl]-N-phenyl-acetamide 450(M⁺) 439 2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep145 3-aminopyridine MS (ion spray)5-yl)-cyclohexyl]-N-pyridin-3-yl-acetamide 450 (M⁺) 4402-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 1453-Methoxy- MS (ion spray)5-yl)-cyclohexyl]-N-(3-methoxy-phenyl)-acetamide phenylamine 480 (M⁺)441 N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Hydroxy-prep 48 MS (ion spray)5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-2-pyridin-3-yl- phenyl-pyridin-543.1 (M+) acetamide 3-yl-acetic acid 442N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin- R-Madelicacid prep 380 MS (ES+) m/z5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-acetamide 466.1 (M + H)+, (ES−)464.2 (M − H)− 443N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin- S-Madelicacid prep 380 MS (ES+) m/z5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-acetamide 466.1 (M + H)⁺, (ES−)464.2 (M − H)⁻ 444N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin- 3-F- prep 380MS (ES+) m/z 5-yl)-cyclohexyl]-2-(3-fluoro-phenyl)-acetamidePhenylacetic 468.1 (M + H)⁺, acid (ES−) 466.2 (M − H)⁻ 445N-[3-(9-Chloro-3-methyl-4-oxo-2,4-dihydro-pyrazolo[4,3- R-Madelic acidprep 399 MS (ES+) m/zc]quinolin-5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-acetamide 465.2 (M + H)⁺446 N-[3-(9-Chloro-3-methyl-4-oxo-2,4-dihydro-pyrazolo[4,3- S-Madelicacid prep 399 MS (ES+) m/zc]quinolin-5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-acetamide 465.2 (M + H)⁺447 6-Hydroxy-pyridine-2-carboxylic acid [3-(9-chloro-3-methyl-6-hydroxy- prep 48 MS (ion spray)4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]- picolinic acid467 (M⁺) amide 448N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Ex 615 prep69 MS (ion spray) Prep 69 was5-yl)-cyclohexyl]-2-hydroxy-2-pyridin-2-yl-acetamide 467 (M⁺)hydro-lized by LiOH in dioxane at rt. 449N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Ex 615 prep69 MS (ion spray) Prep 69 was5-yl)-cyclohexyl]-2-hydroxy-2-pyridin-3-yl-acetamide 467 (M⁺)hydro-lized by LiOH in dioxane at rt. 450{1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 615 prep 69 MS (ionspray) c]quinolin-5-yl)-cyclohexylcarbamoyl]-cyclopentyl)- 543 (M⁺)carbamic acid tert-butyl ester 451{1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Ex 615 prep 69 MS (ionspray) c]quinolin-5-yl)-cyclohexylcarbamoyl]-cyclopropyl}- 515 (M⁺)carbamic acid tert-butyl ester 4522-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid [3-(9- Ex 615 prep 69 MS(ion spray) chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- 469(M⁺) cyclohexyl]-amide 453N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Ex 615 prep69 MS (ion spray) Prep 69 was5-yl)-cyclohexyl]-4-dimethylamino-2-phenoxy-2-phenyl- 613 (M⁺)hydro-lized butyramide by LiOH in dioxane at rt. 454S(+)1R,3S-N-[3-(9-Chloro-3-methyl-4-oxo-5H- (S)(+) Ex 621 ESMS: 466isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentyl]-2- Mandelic acid (M +1)⁺ hydroxy-2-phenyl-acetamide 455R(−)1R,3S-N-[3-(9-Chloro-3-methyl-4-oxo-5H- (R)(−) Ex 621 ESMS: 466isoxazolo[4,3-c]quinolin-5-ylmethyl)cyclopentyl]-2-hydroxy- Mandelicacid (M + 1)⁺ 2-phenyl-acetamide 456 S(+)tert-Butoxycarbonylamino-aceticacid [3-(9-chloro-3- S(+)N-t-BOC- prep 69 MS (ion spray)methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- glycine 623 (M⁺)cyclohexylcarbamoyl]-phenyl-methyl ester 457R(−)tert-Butoxycarbonylamino-acetic acid [3-(9-chloro-3- R(−)N-t-BOC-prep 69 MS (ion spray) methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-glycine 623 (M⁺) cyclohexylcarbamoyl]-phenyl-methyl ester 4582-(4-Acetyl-piperazin-1-yl)-N-[3-(9-chloro-3-methyl-4-oxo- prep 395 prep69 MS(exact mass) Prep 69 was5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-pyridin-3-yl- [M + H]⁺ =hydro-lized acetamide 577.2340 m/z by LiOH in dioxane at rt. 459N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 396 prep69 MS(ES) [M + Prep 69 was5-yl)-cyclohexyl]-2-pyridin-3-yl-2-(pyridin-2-yloxy)- H]⁺ = 544.4 m/z;hydro-lized acetamide [M − H]⁻ = by LiOH in 542.3 m/z dioxane at rt. 460N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 397 prep69 MS(ES) (M + Prep 69 was5-yl)-cyclohexyl]-2-pyridin-3-yl-2-(pyridin-3-yloxy)- H]⁺ = hydro-lizedacetamide 544.3 m/z; [M − by LiOH in H]⁻ = 542.5 m/z dioxane at rt. 461N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- prep 398 prep69 MS(ES) [M + Prep 69 was5-yl)-cyclohexyl]-2-pyridin-3-yl-2-(pyridin-4-yloxy)- H]⁺ = hydro-lizedacetamide 544.3 m/z; [M − by LiOH in H]⁻ = 542.4 m/z dioxane at rt. 4624-tert-Butoxycarbonylamino-butyric acid [3-(9-chloro-3- Ex 471 prep 69MS(ES)[M + methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- H]⁺ = 651.2m/z cyclohexylcarbamoyl]-phenyl-methyl ester 463N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- Hydroxy- prep69 MS(ion spray) 5-yl)-cyclohexyl]-2-hydroxy-2-phenyl- phenyl-pyridin-543.1 (M+) 2-pyridin-3-yl-acetamide 3-yl-acetic acid 465N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- 4-fluoro- Ex634 MS(ion spray) no DMAP 5-yl)-cyclohexyl]-2-(4-fluorophenyl)acetamidephenylacetic 468 (M⁺) acid 466N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- benzoylformicEx 634 MS(ion spray) 5-yl)-cyclohexyl]-2-oxo-2-phenylacetamide acid 464(M⁺). 467 3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Prep43 benzylamine MS(ion spray) yl)-cyclohexanecarboxylic acid benzylamide450 (M⁺) 468 3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-Prep 43 3-(aminoethyl)- MS(ion spray) yl)-cyclohexanecarboxylic acid(pyridin-3-ylmethyl)amide pyridine 451 (M⁺) 4693-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Prep 433-(aminoethyl)- MS(ion spray) yl)-cyclohexanecarboxylic acid(pyridazin-3-ylmethyl)amide pyridine 452 (M⁺) 470N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-L-(+)-mandelic Ex 634 MS(ion spray)5-yl)-cyclohexyl]-2-hydroxy-2-phenylacetamide acid 466 (M⁺) 471N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-D-(−)-mandelic Ex 634 MS(ion spray) 5-yl)-cyclohexyl]-2-phenylacetamideacid 466 (M⁺) 472N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- phenyl- Ex634 MS(ion spray) isomer5-yl)-cyclohexyl]-2-phenyl-2-piperidin-1-ylacetamide piperidin-1-yl- 533(M⁺) 1 = 15.1 mg acetic acid isomer 2 = 8.8 mg 473N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-d/1-2-dimethyl- Ex 634 MS(ion spray)5-yl)-cyclohexyl]-2-dimethylamino-2-phenyl-propionamide amino-3-phenyl-507 (M⁺) propionic acid 474N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin- 2-methoxy-2-Ex 634 MS(ion spray) 5-yl)-cyclohexyl]-2-methoxy-2-phenylpropionamidephenylpropionic 494 (M⁺) acid

[0851] d) Table for Cyclization using KOtBu Ex. # Product StartingMaterial Physical Data 4752-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 5Racemic-68% yield yl)cyclohexyl]-N-(3,4,5-trimethoxyphenyl)acetamide 4762-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 12MS(ES+)m/z = 525.8 Racemicyl)cyclopentyl]-N-(3,4,5-trimethoxypheny)acetamide 4772-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- prep 13MS(ES+)m/z = 525.9, Racemiccyclopentyl]-N-(3,4,5-trimethoxypheny)acetamide 4789-Chloro-3-methyl-5-{3-[2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]- prep43 MS (ion spray) 456.2 (M + 1)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one Racemic 479Cis-2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]-quinolin-5-yl)-prep 158 MS (−ES) m/z 536.9 (M − H), 597.9cyclohexyl]-N-(3,4,5-trimethoxyphenyl)-acetamide (M + OAc).

[0852] e) Table for Cyclization using KHMDS Ex. Starting # ProductMaterial Physical Data Comments 4802-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 18MS(ES+)m/z = 526. quinolin-5-yl)cyclopentyl]-N-(3,4,5- (singleenantiomer) trimethoxyphenyl)acetamide 4812-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 28MS(ES+)m/z = 436. c]quinolin-5-yl)cyclopentyl]-N-(phenyl)acetamideSingle enantiomer 4822-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 28MS(ES+)m/z = 454.c]quinolin-5-yl)cyclopentyl]-N-(4-fluorophenyl)acetamide Singleenantiomer 483 2-[(1R,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-prep 28 MS(ES+)m/z = 437.c]quinolin-5-yl)-cyclopentyl]-N-(pyrid-3-yl)acetamide Single enantiomer484 N-{2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3,- prep 31MS(ES+)m/z = 450 c]quinolin-5-yl))cyclopentyl]ethyl}benzamide Singleenantiomer 485 N-[(1S,3S)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-prep 33 MS(ES+)m/z = 540.c]quinolin-5-yl)cyclopentylethyl]-N-(3,4,5-trimethoxyphenyl)- Singleenantiomer acetamide 486{3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 36MS(ES+)m/z = 525.8 ylmethyl)cyclopentylethyl}-N-(3,4,5-trimethoxy-Racemic phenyl)carboxamide 4879-Chloro-3-methyl-5H-(3-phenylsulfanylmethylcyclohexyl)-5H- prep 78MS(FD): M⁺ 438.3 m/z isoxazolo[4,3-c]quinolin-4-one Racemic 4889-Chloro-3-methyl-5-(3-phenylmethanesulfonylmethyl- prep 82 MS(ES): (M +1)⁺ cyclohexyl)-5H-isoxazolo[4,3-c]quinolin-4-one Racemic 485.5, 487.5m/z 489 [3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep84 MS(ES): (M + 1)⁺ yl)cyclohexyl]methyl benzoate Racemic 450.4, 542.4m/z 490 9-Chloro-3-methyl-5-[3-(2-oxo-3-phenylpropyl)cyclohexyl]-5H-prep 89 MS(ES): [M + H]⁺ = isoxazolo[4,3-c]quinolin-4-one (cis) 449.1m/z, [M − H]⁻ = 447.1 m/z 491[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- prep 84MS (FIA) (m/z) 465.2 cyclohexyl]acetic acid benzyl ester (cis) [M + 1]492 N-[3-(9-Fluoro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep106 MS (FIA) (m/z) 434.3 yl)-cyclohexylmethyl]benzamide (cis) [M + 1]493 N-[3-(9-Chloro-4-oxo-3-phenyl-5H-isoxazolo[4,3-c]quinolin-5- prep107 MS (FIA) (m/z) 512.4 yl)-cyclohexylmethyl]benzamide (cis) [M + 1]494 N-[3-(9-Chloro-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)- prep 108 MS(ES+) (m/z) 436.2 cyclohexylmethyl]benzamide (cis) [M + 1] 495N[3-(6-Iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- prep 109MS (FIA) (m/z) 540.3 cyclohexylmethyl]benzamide (cis) [M − 1] 496N-[3-(8-Iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- prep 110MS (FIA) (m/z) 542.2 cyclohexylmethyl]benzamide (cis) [M + 1] 497N-[3-(7-Fluoro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 111 MS(FIA) (m/z) 434.3 yl)-cyclohexylmethyl]benzamide (cis) [M + 1] 498N-[3-(9-Chloro-3-hexyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 112 MS(FIA) (m/z) 520.3 yl)-cyclohexylmethyl]benzamide (cis) [M + 1] 499phenylmethyl 2-[3-(9-iodo-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 113 MS(FIA) (m/z) 557.0 c]quinolin-5-yl)cyclohexyl]acetate (cis) [M + 1] 5009-Chloro-3-methyl-5-{3-[2-(toluene-3-sulfonyl)-ethyl]- prep 128 MS (ES):(M + 1)⁺ cyclohexyl}-5H-isoxazolo[4,3-c]quinolin-4-one (cis) 499.2,501.2 m/z 501 9-Chloro-3-methyl-5-{(3-phenylthioethyl)-cyclohexyl}-5H-prep 131 MS (FD): M⁺ 452.4 m/z isoxazolo[4,3-c]quinolin-4-one (cis) 5029-Chloro-3-methyl-5-[3-(2-phenylmethanesulfonyl-ethyl)- prep 132 MS(ES): (M + 1)⁺ cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one (cis)499.2, 501.2 m/z 503 9-Chloro-5-{3-[2-(4-fluoro-benzenesulfonyl)-ethyl]-prep 138 MS (ES): (M + 1)⁺cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (cis) 503.1,505.1 m/z 504 phenylmethyl 2-((3R,1R)-3-{[3-(2-chloro-6-fluorophenyl)-5-prep 144 MS (ion spray) 465methylisoxazol-4-yl]carbonyl-amino}cyclohexyl)acetate (cis) (M⁺) 505cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 160ESIMS m/e 432 ³⁵Clyl)-3-[[(1,1-dimethylethyloxy)carbonyl]amino]cyclohexane (M⁺ + 1); 434³⁷Cl (M⁺ + 1) 506[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)- prep 160MS (ES+) m/z 446.1 cyclohexylmethyl]carbamic acid t-butyl ester (trans)(M + H)⁺ 507[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)- prep 160MS (ES+) m/z 446.1 cyclohexylmethyl]carbamic acid t-butyl ester (cis)(M + H)⁺ 508[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)- prep 162MS (ES+) m/z 500.1 cyclohexylmethyl]carbamic acid benzyl ester (cis)(M + H)⁺ 5093-[2-(9-Chloro-3-methyl]-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 167MS (ES+) m/z 554.0yl)-cyclohexyl]-N-(3,4,5-trimethoxy-phenyl)propionamide (M + H)⁺ 510(1R,3S) 3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 170 ESMS: 436(M)⁺, 437 c]quinolin-5-yl)cyclopentanecarboxylic acid benzylamide (M +2)⁺ 511 (1R,3S)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 179ESMS: 436 (M)⁺, 437 c]quinolin-5-yl)-cyclopentylmethyl]benzamide (M +1)⁺ 512 (1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 179ESMS: 436 (M)+, 437 c]quinolin-5-yl)-cyclopentylmethyl]benzamide (M +1)+ 513 (1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 189ESMS: 454 (M)⁺, 455c]quinolin-5-yl)-cyclopentylmethyl]-4-fluorobenzamide (M + 1)⁺, 513 (M +59)⁻ 514 (1S,3R)-Biphenyl-4-carboxylic acid [3-(9-chloro-3-methyl-4-prep 192 ESMS: 512 (M + 1)⁺,oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentylmethyl]amide 570 (M +59)⁻ 515 (1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep195 ESMS: 435 (M − 1)⁻, c]quinolin-5-yl)-cyclopentylmethyl]-nicotinamide495 (M + 59)⁻ 516 (1S,3R)-Furan-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo- prep 198 ESMS: 426 (M + 1)⁺,5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentylmethyl]amide 460 (M + 35)⁻,484 (M + 59)⁻ 517(1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep 201 ESMS:526 (M + 1)⁺,c]quinolin-5-yl)cyclopentylmethyl]-3,4,5-trimethoxybenzamide 584 (M +59)⁻ 518 (1S,3R)-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- prep204 ESMS: 466 (M + 1)⁺, c]quinolin-5-yl)-cyclopentylmethyl]carbamic acidbenzyl ester 524 (M + 59)⁻ 519N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 207ESMS: 540 (M + 1)+,yl)-cyclopentylmethyl]-2-(3,4,5-trimethoxyphenyl)acetamide 574 (M +35)−, 598 (M + 59)− 520N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 208ESMS: 432 (M + 1)+ ylmethyl)-cyclopentyl]carbamic acid t-butyl ester 521[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- prep 209ESMS: 432 (M + 1)+ ylmethyl)-cyclopentyl]carbamic acid t-butyl ester 522trans-[1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]- prep 22 ESIMS m/e432 ³⁵Cl quinolin-5-yl)-3-[[(1,1-dimethylethyloxy)carbonyl]amino]]-(M⁺ + 1); 434 ³⁷Cl cyclohexane (M⁺ + 1) 523N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5- prep 267MS(ES+) (m/z) 441.2 yl)-cyclohexylmethyl]-benzamide [M + 1] 524[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)- prep 269MS(ES+) (m/z) 471.2 cyclohexylmethyl]-carbamic acid benzyl ester [M + 1]525 [3-(9-Chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5- prep 278MS(ES+) (m/z) 346.1 ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester[M-BOC]. 526 N-[3-(9-Chloro-3-diethylamino-4-oxo-5H-isoxazole[4,3- prep280 MS(ES+) (m/z) 507.2 c]quinolin-5-yl)-cyclohexylmethyl]-benzamide[M + 1] 527 N-[3-(9-Chloro-4-oxo-3-pyrroldin-1-yl-5H-isoxazole[4,3- prep281 MS(ES+) (m/z) 505.1 c]quinolin-5-yl)-cyclohexylmethyl]-benzamide[M + 1] 528 N-[3-(9-Chloro-3-ethylamino-4-oxo-5H-isoxazole[4,3- prep 280MS(ES+) (m/z) 479.1 c]quinolin-5-yl)-cyclohexylmethyl]-benzamide [M + 1]529 N-[3-(9-Chloro-3-ethylsulfanyl-4-oxo-5H-isoxazole[4,3- prep 283MS(ES+) (m/z) 496.1 c]quinolin-5-yl)-cyclohexylmethyl]-benzamide [M +1]. 530 N-[3-(9-Chloro-4-oxo-3-phenylamino-5H-isoxazole[4,3- prep 278MS(ES+) (m/z) 527.2 c]quinolin-5-yl)-cyclohexylmethyl]-benzamide [M +1]. 531 N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5- prep316 MS(ES+) (m/z) 441.2 yl)-cyclohexylmethyl]-benzamide [M + 1]. 532[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)- prep 318MS(ES+) (m/z) 471.2 cyclohexylmethyl]-carbamic acid benzyl ester [M +1]. 533 [3-(9-Chloro-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5- prep327 MS(ES+) (m/z) 346.1 ylmethyl)-cyclohexyl]-carbamic acid tert-butylester [M-BOC]. 534 N-[3-(9-Chloro-3-diethylamino-4-oxo-5H-isoxazole[4,3-prep 329 MS(ES+) (m/z) 507.2c]quinolin-5-yl)-cyclohexylmethyl]-benzamide [M + 1]. 535N-[3-(9-Chloro-4-oxo-3-pyrroldin-1-yl-5H-isoxazole[4,3- prep 330 MS(ES+)(m/z) 505.1 c]quinolin-5-yl)-cyclohexylmethyl]-benzamide [M + 1]. 536N-[3-(9-Chloro-3-ethylamino-4-oxo-5H-isoxazole[4,3- prep 331 MS(ES+)(m/z) 479.1 c]quinolin-5-yl)-cyclohexylmethyl]-benzamide [M + 1]. 537N-[3-(9-Chloro-3-ethylsulfanyl-4-oxo-5H-isoxazole[4,3- prep 332 MS(ES+)(m/z) 496.1 c]quinolin-5-yl)-cyclohexylmethyl]-benzamide [M + 1]. 538N-[3-(9-Chloro-4-oxo-3-phenylsulfanyl-5H-isoxazole[4,3- prep 328 MS(ES+)(m/z) 544.2 Prep 328 was c]quinolin-5-yl)-cyclohexylmethyl]-benzamide[M + 1]. initially treated with Na thiophenoxide (5eq) in DMF. 539N-[3-(9-Chloro-4-oxo-3-phenylamino-5H-isoxazole[4,3- prep 328 MS(ES+)(m/z) 527.2 Prep 328 was c]quinolin-5-yl)-cyclohexylmethyl]-benzamide[M + 1]. initially treated with aniline (20eq) in DMF. 540[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Prep 333MS(ES+) (m/z) 346.3 ylmethyl)-cyclohexyl]-carbamic acid tert.-butylester [M-BOC]. 541 N-{2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]-Prep 33 MS(ES+)m/z = 540.quinolin-5-yl)-cyclopentyl]-ethyl}-3,4,5-trimethoxy-benzamide Singleenantiomer 541a{3-[(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Prep 337MS(ES+)m/z = 525.8 yl))methyl]cyclopentyl}-N-(3,4,5-trimethoxyphenyl)-carboxamide 542[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)- Prep 338MS(ES+)m/z = 402.9. cycloheptyl]-acetic acid methyl ester 543N-{2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3- Prep 31 MS(ES+)m/z =450. c]quinolin-5-yl)-cyclopentyl]-ethyl}-benzamide 5442-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Prep 337MS(ES+)m/z = 526. yl)-cyclopentyl]-N-(3,4,5-trimethoxyphenyl)-acetamide(Single enantiomer) 545[3-(9-Chloro-3-methyl-4-oxo-3,4-dihydro-imidazo[4,5- Ex 405 MS (ES+)(m/z) 479.3 c]quinolin-5-yl)-cyclohexylmethyl]-carbamic acid benzylester [M + 1]

[0853] f) Table for Arylation: Ex. # Product Starting Material AStarting Material B Physical Data 5469-Chloro-3-methyl-5-[3-(quinolin-2-ylaminomethyl)- Ex 6192-chloroquinoline MS(FIA) (m/z)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one 473.1 (M + 1) 5479-Chloro-3-methyl-5-[3-[(5-nitro-pyridin-2-ylamino)-methyl]- Ex 6192-chloro-6- MS(FIA) (m/z) cyclohexyl}-5H-isoxazolo[4,3-c]quinolin-4-onenitropyridine 466.1 (M − 1) 5482-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex 6192-chloro-3- MS(FIA) (m/z) yl)cyclohexylmethyl]amino}-nicotinonitrilenitrilepyridine 448.1 (M + 1) 5499-Chloro-3-methyl-5-{3-[(5-nitropyridin-2-ylamino)methyl]- Ex 6192-chloropyrimidine MS(FIA) (m/z)cyclohexyl}-5H-isoxazolo[4,3-c]quinolin-4-one 424.1 (M + 1) 5509-Chloro-5-{3-[4-chloropyrimidin-2-ylamino)- Ex 619 2,4- MS(FIA) (m/z)methyl]cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-dichloropyrimidine 458.4 (M + 1) one isomers were and separated9-Chloro-5-{3-[2-chloropyrimidin-4-ylamino)-methyl]-cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (racemic) 5519-Chloro-5-{3-[(6-chlorobenzothiazol-2-ylamino)methyl]- Ex 6192,6-dichlorobenzothiazole MS(FIA) (m/z)cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one 515.2 (M + 1) 5525-[3-(Benzothiazol-2-ylaminomethyl)-cyclohexyl}-9-chloro-3- Ex 6192-chlorobenzothiazole MS(FIA) (m/z)methyl-5H-isoxazolo[4,3-c]quinolin-4-one 479.1 (M + 1) 5535-[3-(Benzooxazol-2-ylaminomethyl)cyclohexyl}-9-chloro-3- Ex 6192-chlorobenzooxazole MS(FIA) (m/z)methyl-5H-isoxazolo[4,3-c]quinolin-4-one 463.3 (M + 1)

[0854] g) Table for Chiral Separation: Ex. Starting # Product MaterialPhysical Data 5542-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex432 Retention Time = 8.56 minutesyl))cyclohexyl]-N-(3,4,5-trimethoxyphenyl)acetamide 5552-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex432 Retention Time = 16.08 minutesyl))cyclohexyl]-N-(3,4,5-trimethoxyphenyl)acetamide 556N-{[(1R,3S)-3-(9-chloro-3-methyl-4-oxo(5-hydroisoxazolo[4,3- Ex 116Retention Time = 9.232 min c]quinolin-5-yl))cyclohexyl]methyl}benzamide557N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5- Ex116 Retention Time = 12.704 min yl))cyclohexyl]methyl}benzamide 5582-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5- Ex479 MS (−ES) m/z 536.9 (M − H), 597.9yl))cyclohexyl]-N-(3,4,5-trimethoxyphenyl)acetamide (M + OAc) 5592-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5- Ex479 MS (−ES) m/z 536.9 (M − H), 597.9yl))cyclohexyl]-N-(3,4,5-trimethoxyphenyl)acetamide (M + OAc) 560N-{[(1S,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5- Ex506 MS (+ES) m/z 446 (M + H)+, 463yl))cyclohexyl]methyl}(t-butoxy)carboxamide (M + NH3)+, (−ES) 480 (M −H + Cl)−, 504 (M − H + OAc)− 561N-{[(1R,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin- Ex506 MS (+ES) m/z 446 (M + H)+, 4635-yl))cyclohexyl]methyl}(t-butoxy)carboxamide (M + NH3)+, (−ES) 480 (M −H + Cl)−, 504 (M − H + OAc)− 562N-{[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5- Ex507 MS (+ES) m/z 446 (M + H)+, 463yl))cyclohexyl]methyl}(t-butoxy)carboxamide (M + NH3)+, (−ES) 480 (M −H + Cl)−, 504 (M − H + OAc)− 563N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5- Ex507 MS (+ES) m/z 446 (M + H)+, 463yl))cyclohexyl]methyl}(t-butoxy)carboxamide (M + NH3)+, (−ES) 480 (M −H + Cl)−, 504 (M − H + OAc)− 5643-[(1S,2S)-2-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5- Ex618 MS (+ES) 553.9, 555.9 (M + H)+yl))cyclohexyl]-N-(3,4,5-trimethoxyphenyl)propanamide 5653-[(2S,1R)-2-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5- Ex618 MS (+ES) 553.9, 555.9 (M + H)+yl))cyclohexyl]-N-(3,4,5-trimethoxyphenyl)propanamide

Example 566(2R)-N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclo-hexylmethyl]-2-amino-3-(phenylmethoxy)propanamide

[0855] A solution of(2R)-N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-2-[(t-butoxy)carbonylamino]-3-(phenylmethoxy)-propanamide,80 mg (0.13 mmol) in 10 mL of acetic acid saturated with hydrochloricacid was stirred for 2 h at ambient temperature and concentrated todryness. The residue was dissolved in toluene and concentrated todryness and dried under vacuum to yield a quantitative yield of thedesired product as a white foam. ¹H-NMR is consistent with structure. MS(ion spray) 523.2 (M+).

Example 567N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-3-aminobenzamide

[0856] To a solution containing 620 mg (1.25 mmol) of a compound fromExample 48 in 15 mL of THF was added 848 mg (3.75 mmol) of SnCl₂.2H₂O atroom temperature. To the resulting suspension was added 1.0 mL ofconcentrated HCl and the reaction was stirred for 15 hours at roomtemperature. The reaction was diluted with 100 mL of ethyl acetate andwashed once with brine. The organic solution was separated, dried andconcentrated to give a white foam. This crude material was purified byflash chromatography, using ethyl acetate as the eluent. The majorfractions were combined and concentrated in vacuo to give 400 mg of awhite amorphous solid. MS(FIA) m/z=465.2.

Example 568N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclobexylmethyl]-4-aminobenzamide

[0857] The title compound was prepared from the compound from Example110 according to the conditions for the preparation of Example 567.MS(FIA) m/z=465.2.

Example 569N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cyclohexylmethyl]-3-(4-methyoxy)benzyloxybenzamide

[0858] To a suspension of 150 mg (0.581 mmol) of a compound frompreparation 56 in 10 mL of CH₂Cl₂ was added 2 drops of DMF, followed bythe addition of 51 μL (0.581 mmol) of oxalyl chloride. The reaction wasstirred at room temperature and evolution of CO gas was noted. Thereaction was stirred an additional 30 minutes at room temperature andthen concentrated in vacuo. The resulting acid chloride was dissolved in10 mL of CH₂Cl₂. In a separate flask, 250 mg (0.528 mmol) of thecompound from Example 302, was suspended in 10 mL of CH₂Cl₂. To this wasadded 110 μL of triethylamine and the resulting solution was added tothe flask containing the acid chloride, followed by the addition of anadditional 110 μL of triethylamine. The reaction was stirred at roomtemperature for 15 hours, diluted with 50 mL of ethyl acetate and washedtwice with 1N HCl, twice with 1N NaOH, dried over sodium sulfate andconcentrated in vacuo to give a white amorphous solid. This material wasrecrystallized from toluene to give 190 mg of a white amorphous solid.MS(ES+) m/z=586.19.

Example 570N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cyclohexylmethyl]-3-hydroxybenzamide

[0859] To a solution containing 50 mg (0.0853 mmol) of a compound fromExample 569 in 2 mL of CH₂Cl₂ was added 2 mL of TFA. The reaction wasstirred at room temperature for 18 hours and concentrated in vacuo. Theresulting crude solid was recrystallized from toluene to give a whiteamorphous solid. MS(ES+) m/z=466.1.

Example 571N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cyclohexylmethyl]-4-(4-methoxy)benzyloxybenzamide

[0860] The title compound was prepared from methyl 4-hydroxybenzoateaccording to the conditions for the preparation of Example 569. MS(ES+)m/z=586.19.

Example 572N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cyclohexylmethyl]-4-hydroxybenzamide

[0861] The title compound was prepared from a compound of Example 571according to the conditions for the preparation of Example 570. MS(ES+)m/z=466.1.

Example 573N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-benzenesulfonamide

[0862]N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]benzenethioamide(0.78 g; 1.59 mmol) was dissolved in anhydrous dimethylformamide (16mL), chilled to −20° C. for 10 min, and mixed with 0.5 M potassiumbis(trimethylsilyl)amide in toluene (7.0 mL; 3.5 mmol; 2.2 equiv). Thereaction solution was stirred 10 min at −20° C. and another 35 min atroom temperature. After quenching the reaction with 1 M HCl (50 mL), thesolution was extracted with ethyl acetate (twice). The organic layer waswashed with saturated NaCl_((aq)) (twice), then dried with Na₂SO_(4(s)),filtered, and concentrated to dryness by rotary evaporation. Theresulting white solid was purified by radial chromatography (threeconsecutive times) on a 4 mm thick silica gel rotor with a 5%tetrahydrofuran/dichloromethane (v/v) mobile phase and then twice with a50% ethyl acetate/hexanes (v/v) mobile phase. Concentration ofproduct-containing fractions produced 11 mg (2% yield) of a white solid.MS(ES) calc'd: [M+H]⁺=472.0 m/z, [M−H]⁻=470.0 m/z. Found: 471.9 m/z,470.0 m/z.

Example 574N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]benzenesulfonamide

[0863]N-[3-(9-Chloro-3-methyl-4-oxo-SH-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]benzenethioamide(0.41 g; 0.83 mmol) was dissolved in anhydrous dimethylformamide (8 mL),chilled to −20° C. for 10 min, and mixed with 0.5 M potassiumbis(trimethylsilyl)amide in toluene (4 mL; 1.83 mmol; 2.2 equiv). Thereaction solution was stirred 10 min at −20° C. and another 35 min atroom temperature. After quenching the reaction with 1 M HCl (50 mL), thesolution was extracted with ethyl acetate (twice). The organic layer waswashed with saturated NaCl_((aq)) (twice), then dried with Na₂SO₄(s),filtered, and concentrated to dryness by rotary evaporation. Theresulting white solid was purified by radial chromatography on a 4 mmthick silica gel rotor with a 40% ethyl acetate/hexanes (v/v) mobilephase. Product containing fractions were combined, concentrated andfurther purified by radial chromatography (twice) on a 2 mm thick silicagel rotor with a 50% ethyl acetate/hexanes (v/v) mobile phase.Concentration of product-containing fractions produced 53 mg (14% yield)of a white solid. MS(ES) calc'd: [M+H]⁺=472.0 m/z, [M−H]⁻=470.0 m/z.Found: 472.0 m/z, 470.2 m/z.

Example 5754-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexanecarboxylicacid 3,4,5-trimethoxybenzylamide

[0864] The compound from preparation 72 (0.40 g, 0.00098 mol) wascombined with THF (5 mL), MeOH (2 mL), water (5 mL) and 2N NaOH (5 mL)and the mixture stirred at ambient temperature until hydrolysis wascomplete. The mixture was concentrated in vacuo and the residue taken upin water and carefully acidified using aq 1N HCl. The aqueous mixturewas extracted with ethyl acetate and the combined extracts were driedover sodium sulfate. Concentration in vacuo left the crude acid whichwas combined with 1-(3-dimethyl-aminopropyl-3-ethylcarbodiimidehydrochloride (0.186 g, 0.00097 mol), 1-hydroxy-7-azabenzotriazole(0.133 g, 0.00098 mol) and 3,4,5-trimethoxybenzylamine (0.193 g, 0.00098mol) in DMF (15 mL) and the resulting mixture stirred overnight atambient temperature. The mixture was concentrated in vacuo and theresidue taken up in water. The aqueous mixture was extracted with CH₂Cl₂and the combined extracts dried over sodium sulfate and concentrated invacuo. The resulting residue was chromatographed over silica gel usingCH₂Cl₂/THF as eluent which allowed for isolation of 0.120 g (40%) of thedesired product as a yellowish solid. MS(ES): (M+1)+540.4 m/z.

Example 576-5775-(3-Benzenesulfinylmethylcyclohexyl)₉-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one&5-(3-Benzenesulfonylmethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0865] The compound from Example 487 (0.20 g, 0.00046 mol) was dissolvedin CH₂Cl₂ (30 mL) and the mixture cooled under a nitrogen atmosphere ina dry ice/acetone bath. Then 3-chloroperoxybenzoic acid (50%, 0.16 g,0.00046 mol) was added and the mixture stirred for 2 h while warmingnear ambient temperature. The mixture was concentrated and the residuechromatographed over silica gel using CH₂Cl₂/MeOH as eluent whichallowed for isolation of both the sulfoxide (0.132 g, 63%). MS(ES):(M+1)⁺ 455.1, 457.3 m/z, and the sulfone (0.078 g, 36%) MS(ES): (M+1)⁺471.2 m/z.

Example 5789-Chloro-5-[3-(2-methoxyimino-3-phenylpropyl)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0866] To a solution of the compound from Example 490 in denaturedethanol (6 mL) was added a solution of methoxyamine hydrochloride (74.5mg; 0.892 mmol; 4 equiv) and sodium acetate (73.1 mg; 0.892 mmol; 4equiv) in water (1 mL). The cloudy reaction mixture became clear andcolorless when heated to reflux. After 1.6 h the reaction solution wasconcentrated to dryness by rotary evaporation. The resulting solid wasdissolved in dichloromethane and the organic layer was washed with water(once), washed with saturated NaCl_((aq)) (once), dried withNa₂SO_(4(s)), filtered, and concentrated to dryness by rotaryevaporation. The product was isolated as a mixture of oxime isomers byradial chromatography on a 2 mm thick silica gel rotor with a 2%acetonitrile/dichloromethane (v/v) mobile phase. A clear, colorless oil(92 mg; 86%) was obtained after concentration of the appropriatefractions. TOF-MS(ES) calc'd: [M+H]⁺=478.1897 m/z. Found: 478.1891 m/z.

Example 5792-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl]-N-4-methoxyphenylacetamide

[0867] To a 7 mL scintillation vial containing 0.10 g (0.254 mmol) of acompound from preparation 95 in 3 mL of methylene chloride was added0.086 g (0.509 mmol) p-anisidine followed by 0.10 mL of triethylamine.The reaction was shaken overnight, passed through a 2 g SCX column,eluting with methylene chloride and the racemic cis product crystallizedout of one of the fractions giving 0.054 g (44%). MS(FIA) m/z=480.1.

Example 5802-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl]-N-2-methoxy-5-nitrophenylacetamide

[0868] The title compound was prepared from a compound of preparation 95and 2-methoxy-5-nitroaniline triethylamine in a manner similar to thatof Example 579 to yield 0.051 g (38%). MS(FIA) m/z=525.2.

Example 5819-Chloro-3-methyl-5-[3-(2-oxo-pyrrolidin-1-ylmethylcyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

[0869] To a stirred solution of the compound of Example 105 (148 mg,0.33 mmol) in DMF (3 mL) and THF (4 mL) was added NaH (41 mg, 1.0 mmol,60% in mineral oil) and stirred at r.t. for 1.5 hours. The reactionmixture was diluted with ethyl acetate, washed (brine), dried (Na₂SO₄),filtered and concentrated. Column chromatography (silica gel, ethylacetate) gave 82 mg, 60%. MS(FIA) (m/z) 414.2 (M+1).

Example 582N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl-2-(3,4,5-trimethoxyphenylmethyl)]acetamide

[0870] To a stirred solution ofN-[(1S,4R)-4-(9-chloro-3-methyl-4-oxo(5-hydroisoxazolo[4,3-c]quinolin-5-yl))cyclopent-2-enyl]-2-(3,4,5-trimethoxyphenyl)-acetamide(55 mg, 0.11 mmol) in DMF (5 mL) was added Rh/C (5%) and treated with H₂and stirred at r.t. for 18 hours. The mixture was filtered. The filtratewas diluted with EtOAc, washed (brine), dried (Na₂SO₄), filtered andconcentrated. Column chromatography (silica gel, hexanes/ethyl acetate,gradient) gave the title compound 38 mg, 69%. MS(FIA) (m/z) 526.3 (M+1).

Example 583N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclopentyl-2-(3-fluorophenylmethyl)]acetamide

[0871] To a stirred solution ofN-[(1S,4R)-4-(9-chloro-3-methyloxo(5-hydroisoxazolo[4,3-c]quinolin-5-yl))cyclopent-2-enyl)-2-(3,4,5-trimethoxyphenyl)acetamide (49 mg, 0.11 mmol) in EtOAc (5 mL) was added Rh/C (5%,catalytic amount) and treated with H₂ and stirred at r.t. for 18 hours.The mixture was filtered. The filtrate was diluted with EtOAc, washed(brine), dried (Na₂SO₄), filtered and concentrated. Columnchromatography (silica gel, hexanes/ethyl acetate, gradient) gave thetitle compound 48 mg, 97%. MS(FIA) (m/z) 454.1 (M+1).

Example 584 and 5853-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)cyclohexane-carboxylicacid (3,4,5-trimethoxyphenyl)

[0872] A compound from preparation 101 (0.2 g, 0.54 mmol), 1 N NaOH(1.32 ml, 1.32 mmol), and MeOH (8 ml) were heated at 50° C. for 2 h. Thereaction was cooled to r.t., acidified to pH<3, and concentrated usingbenzene to azeotrope. The residue, EDCI (0.2 g, 1.07 mmol),3,4,5-trimethoxyaniline (0.119 g, 0.65 mmol), DMAP (0.013 g, 0.11 mmol),and dichloromethane (5.5 ml) were mixed under N₂. The mixture wasdiluted with EtOAc, washed, dried, filtered, and concentrated to give585 (0.05 g, 17%) and 584 (0.07 g, 24%) after radial chromatography(silica gel, 5% acetone/dichloromethane). 585: MS(FIA) (m/z) 540.4[M+1]. 584: MS(FIA) (m/z) 540.4 [M+1].

Example 5863-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)cyclohexane-carboxylicacid (2-methoxy-5-nitrophenyl)

[0873] In a fashion similar to that described for Example 585, methyl3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexanecarboxylate (0.2 g, 0.54 mmol), 1 N NaOH (1.32 ml, 1.32 mmol), MeOH (8ml), EDCI (0.2 g, 1.07 mmol), 2-methoxy-5-nitroaniline (0.11 g, 0.65mmol), DMAP (0.013 g, 0.11 mmol), dichloromethane (5.5 ml) gave b (0.052g, 18%) and a (0.068 g, 24%) after radial chromatography (silica gel, 2%acetone/dichloromethane).

[0874] b: MS(FIA) (m/z) 523.1 [M−1].

[0875] a: MS(FIA) (m/z) 523.1 [M−1].

Example 5879-Chloro-5-[3-(4,4-dimethyl-4,5-dihydro-oxazol-2-ylmethyl)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4one

[0876] The compound from preparation 43 (0.2 g, 0.54 mmol) was dissolvedin dichloromethane (3.6 ml) followed by addition of oxalyl chloride(0.108 ml, 1.08 mmol) and DMF (0.005 ml). After 1 h of stirring, thevolatiles were removed. The residue was dissolved in dichloromethane(1.5 ml) and 2-amino-2-methyl-1-propanol (0.1 ml, 1.08 mmol) was added.The reaction was stirred for 3 h then concentrated. The reaction wasdissolved in thionyl chloride (2 ml) and stirred for 40 min. Thereaction was concentrated, added 0.1 N NaOH, and extracted with EtOAc(3×). The combined organic layers were washed (brine), dried (MgSO₄),filtered, and concentrated. Column chromatography (silica gel,hexanes/EtOAc gradient) gave the title compound (0.06 g, 26%). MS(FIA)(m/z) 428.2 [M+1].

Example 588 & 5895-(3-Benzooxazol-2-ylmethyl-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]-quinolin-4-one&2-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-N-(2-hydroxyphenyl)acetamide

[0877] In a fashion similar to that described for Example 587, compoundfrom preparation 43 (0.159 g, 0.423 mmol), oxalyl chloride (0.073 ml,0.84 mmol), dichloromethane (2.8 ml), DMF (0.005 ml), 2-aminophenol (0.2g, 1.07 mmol), dichloromethane (1.5 ml), and thionyl chloride (2 ml)gave the title compounds5-(3-benzooxazol-2-ylmethyl-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one,588, (0.089 g, 47%) and2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-N-(2-hydroxy-phenyl)-acetamide,589, (0.031 g, 16%) after column chromatography (silica gel,acetone/dichloromethane gradient). 588: MS(FIA) (m/z) 448.1 [M+1]. 589:MS(FIA) (m/z) 466.2 [M+1].

Example 5909-Chloro-3-methyl-5-[3-(4-phenyl-4,5-dihydro-oxazol-2-ylmethyl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

[0878] In a fashion similar to that described for Example 587, acompound from preparation 43 (0.159 g, 0.423 mmol), oxalyl chloride(0.073 ml, 0.84 mmol), dichloromethane (2.8 ml), DMF (0.005 ml),R-(−)-2-phenylglycinol (0.115 g, 0.884 mmol), dichloromethane (1.5 ml),and thionyl chloride (2 ml) gave the title compound (0.105 g, 52%) aftercolumn chromatography (silica gel, acetone/dichloromethane gradient).MS(FIA) (m/z) 476.1 [M+1].

Example 5919-Chloro-3-methyl-5-[3-(4-phenyl-4,5-dihydro-oxazol-2-ylmethyl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

[0879] In a fashion similar to that described for Example 587, compoundfrom preparation 43 (0.159 g, 0.423 mmol), oxalyl chloride (0.073 ml,0.84 mmol), dichloromethane (2.8 ml), DMF (0.005 ml),S-(+)-2-phenylglycinol (0.115 g, 0.84 mmol), dichloromethane (1.5 ml),and thionyl chloride (2 ml) gave the title compound (0.07 g, 35%) aftercolumn chromatography (silica gel, acetone/dichloromethane gradient).MS(FIA) (m/z) 476.1 [M+1].

Example 5925-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-4,5-dihydroisoxazolo[4,3-c]-quinoline-8-carboxylicacid methyl ester

[0880] To a mixture of Example 496 (0.034 g, 0.063 mmol), acetonitrile(8 ml), MeOH (3 ml), Et₃N (0.15 ml, 0.2 mmol) submerged in a 65° C. oilbath was added PdCl₂(dppf) (0.003 g, 0.003 mmol) under CO atmosphere(balloon). The reaction was stirred for 5 h. The reaction was cooled toroom temperature and concentrated. The residue was diluted with EtOAc,washed (H₂O then brine), dried (MgSO₄), filtered, and concentrated.Column chromatography (silica gel, acetone/dichloromethane gradient)gave the title compound (0.021 g, 70%). MS(ES+) (m/z) 474.2 [M+1].

Example 5935-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-4,5-dihydroisoxazolo[4,3-c]-quinoline-6-carboxylicacid methyl ester

[0881] In a fashion similar to that described for Example 592,N-[3-(6-Iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-benzamide(0.048 g, 0.089 mmol), acetonitrile (10 ml), MeOH (5 ml), Et₃N (0.04 ml,0.267 mmol), and PdCl₂(dppf) (0.004 g, 0.004 mmol) gave the titlecompound (0.035 g, 83%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(FIA) (m/z) 472.3 [M−1].

Example 594[3-(9-Iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-5-yl)cyclohexylmethyl]-carbamicacid t-butyl ester

[0882] To a solution of phenylmethyl2-[(1R,3S)-3-(9-iodo-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]acetate(1 g, 2.14 mmol) and t-BuOH (15 ml) submerged in a 50° C. oil bath wasadded Et₃N (0.386 ml, 2.78 mmol) and DPPA (0.6 ml, 2.78 mmol) under N₂.This solution was heated at reflux overnight. The solvents were removedin vacuum and the residue was chromatographed (silica gel, EtOAc/hexanesgradient) to give the title compound (0.47 g, 40%). MS(FIA) (m/z) 538.3[M+1], 438.0 [M−BOC].

Example 595N-[3-(3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]benzamide

[0883] To a mixture of Example 106 (0.07 g, 0.129 mmol) andtetrakis(triphenyl-phosphine)palladium (0.015 g, 0.0129 mmol) in toluene(1.3 ml) under N₂ was added tributyltin hydride (0.042 ml, 0.155 mmol)and heated at 80° C. for 17 h. Added more tributyltin hydride (0.069 ml,0.258 mmol) to the mixture and heated at this temperature for 24 h. Thereaction was cooled to room temperature, applied to a 10, silica gelcolumn, and elution (acetone/dichloromethane gradient) gave the titlecompound (0.02 g, 38%).

[0884] MS(ES+) (m/z) 416.2 [M+1].

Example 596N-{3-[9-(4-Methoxyphenyl)-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

[0885] To a mixture of Example 106 (0.1 g, 0.185 mmol),tetrakis(triphenyl-phosphine)palladium (0.043 g, 0.037 mmol), and4-methoxyphenylboronic acid (0.7 g, 0.46 mmol) in dioxane (2 ml) underN2 was added Na₂CO₃(aq) (0.185 ml, 0.37 mmol) and heated at reflux for72 h. The reaction was cooled to room temperature, diluted with EtOAc,washed (H₂O then brine), dried (MgSO₄), filtered, and concentrated.Radial chromatography (silica gel, 33.3% EtOAc/hexanes) gave the titlecompound (0.057 g, 59% o). MS(FIA) (m/z) 522.2 [M+1].

Example 5975-[3-(Benzoylamino-methyl)-cyclohexyl]-3-methyl-4-oxo-5-hydro-isoxazolo[4,3-c]quinoline-9-carboxylicacid methyl ester

[0886] In a fashion similar to that described for Example 272, acompound from Example 106 (0.88 g, 1.63 mmol), acetonitrile (60 ml),MeOH (20 ml), Et₃N (0.68 ml, 4.89 mmol), and PdCl₂(dppf) (0.066 g, 0.08mmol) gave the title compound (0.687 g, 89%) after column chromatography(silica gel, acetone/dichloromethane gradient).

[0887] MS(FIA) (m/z) 474.1 [M+1].

Example 5985-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicacid

[0888] A compound from Example 597 (0.35 g, 0.74 mmol), 5.0 N NaOH (2.4ml, 11.84 mmol), and dioxane (7 ml) were allowed to react for 3 h at 90°C. in a fashion similar to that of Example 472, give the title compound(0.28 g, 85%). MS(ES+) (m/z) 460.2 [M+1].

Example 5995-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicacid amide

[0889] To a solution of Example 598, (0.05 g, 0.11 mmol), EDCI (0.032 g,0.165 mmol), and HOBt (0.023 g, 0.165 mmol) in DMF (1.5 ml) under N₂ wasadded NH₄Cl (0.009 g, 0.165 mmol) and diisopropylamine (0.046 ml, 0.33mmol). The reaction was stirred overnight. The mixture was diluted withEtOAc, washed (1.0 N HCl saturated with NaCl), dried (MgSO₄), filtered,and concentrated. Column chromatography (silica gel, hexanes/EtOAcgradient) gave the title compound (0.024 g, 48%). MS(ES+) (m/z) 459.1[M+1].

Example 6005-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyloxoSH-isoxazolo[4,3-c]quinoline-9-carboxylicacid diethylamide

[0890] In a fashion similar to that described for Example 596, acompound from Example 598 (0.05 g, 0.11 mmol), EDCI (0.032 g, 0.165mmol), HOBt (0.023 g, 0.165 mmol), DMF (1.5 ml), and diethylamine (0.017ml, 0.165 mmol) gave the title compound (0.039 g, 68%) after columnchromatography (silica gel, acetone/dichloromethane gradient).

[0891] MS(ES+) (m/z) 515.2 [M+1].

Example 6015-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicacid ethyl ester

[0892] To a solution of Example 598, (0.05 g, 0.11 mmol) in DMF (1 ml)under N₂ was added iodoethane (0.062 ml, 0.33 mmol) and Cs₂CO₃ (0.036 g,0.11 mmol). The mixture was stirred overnight, diluted with EtOAc,washed (H₂O then brine), dried (MgSO₄), filtered, and concentratedColumn chromatography (silica gel, acetone/dichloromethane gradient)gave the title compound (0.043 g, 80%). MS(FIA) (m/z) 488.4 [M+1).

Example 6025-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-SH-isoxazolo[4,3-c]quinoline-9-carboxylicacid benzyl ester

[0893] In a fashion similar to that described for Example 601, acompound from Example 598 (0.05 g, 0.11 mmol), benzyl bromide (0.039 ml,0.33 mmol), Cs₂CO₃ (0.036 g, 0.11 mmol), and DMF (1 ml) gave the titlecompound (0.051 g, 85%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(FIA) (m/z) 548.3 [M−1].

Example 6035-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicacid ethoxycarbonylmethyl ester

[0894] In a fashion similar to that described for Example 601, acompound from Example 598 (0.05 g, 0.11 mmol), ethyl bromoacetate (0.036ml, 0.33 mmol), Cs₂CO₃ (0.036 g, 0.11 mmol), and DMF (1 ml) gave thetitle compound (0.054 g, 90%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(FIA) (m/z) 546.2 [M+1].

Example 6045-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicacid isopropyl ester

[0895] In a fashion similar to that described for Example 601, acompound from Example 598 (0.05 g, 0.11 mmol), 2-iodopropane (0.033 ml,0.33 mmol), Cs₂CO₃ (0.036 g, 0.11 mmol), and DMF (1 ml) gave the titlecompound (0.021 g, 38%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(ES+) (m/z) 502.2 [M+1].

Example 6055-[3-(Benzoylamino-methyl)-cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicacid ethylamide

[0896] In a fashion similar to that described for Example 599, acompound from Example 598 (0.05 g, 0.11 mmol), EDCI (0.032 g, 0.165mmol), HOBt (0.023 g, 0.165 mmol), DMF (1.5 ml), ethylamine (0.55 ml,1.1 mmol), and diisopropylethylamine (0.06 ml, 0.33 mmol) gave the titlecompound (0.003 g, 6%) after column chromatography (silica gel,acetone/dichloromethane gradient). MS(ES+) (m/z) 487.3 [M+1].

Example 6065-[3-(Benzoylaminomethyl)cyclohexyl]-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinoline-9-carboxylicacid methyl amide

[0897] To a solution of Example 598 (0.05 g, 0.11 mmol) in toluene (1.5ml) under N₂ was added thionyl chloride (0.5 ml) and heated at refluxfor 3 h. The solution was concentrated using toluene to azeotrope. Theresidue was dissolved in dichloromethane (2 ml) under N₂ and addedmethylamine (0.55 ml, 1.1 mmol) and DMAP (0.025 g, 0.22 mmol). Thereaction was stirred overnight, diluted with dichloromethane, washed(0.1 N HCl, H₂O, and brine), dried (MgSO₄), filtered, and concentrated.Column chromatography (silica gel, acetone/CH₂Cl₂ gradient) gave thetitle compound (0.029 g, 56%). MS(ES+) (m/z) 473.2 [M+1].

Example 607N-{3-[9-(4,5-Dihydro-oxazol-2-yl)-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl]-cyclohexylmethyl}benzamide

[0898] To a solution of Example 598 (0.1 g, 0.22 mmol) in toluene (4 ml)under N₂ was added thionyl chloride (1 ml) and heated at reflux for 3 h.The solution was concentrated using toluene to azeotrope and the residuewas dissolved in dichloromethane (4 ml) under N₂. Ethanolamine (0.131ml, 2.2 mmol) and DMAP were added to the reaction and stirred overnight.The mixture was diluted with dichloromethane, washed (5% NaHCO₃, H₂O,and brine), dried (MgSO₄), filtered, and concentrated. The residue wasdissolved in thionyl chloride (2 ml), stirred overnight, andconcentrated. The crude material was purified by column chromatography(silica gel, acetone/CH₂Cl₂ gradient) to give the title compound (0.01g, 10%). MS(ES+) (m/z) 485.2 [M+1], 521.2 [M+HCl].

Example 608N-[3-(9-Hydroxymethyl-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

[0899] To a solution of Example 598 (0.01 g, 0.022 mmol) in toluene (0.4ml) under N₂ was added thionyl chloride (0.1 ml) and heated at refluxfor 3 h. The solution was concentrated using toluene to azeotrope andthe residue was dissolved in dichloromethane (0.5 ml). To this solutionwas added NaBH₄ (0.008 g, 0.22 mmol) in THF (0.5 ml) and stirredovernight. The mixture was diluted with MeOH (1 ml) and EtOAc, washed(0.1 N NaOH, H₂O, and brine), dried (MgSO₄), filtered, and concentratedto give the title compound (0.005 g, 53%) without further purification.MS(ES+) (m/z) 446.2 [M+1].

Example 609N-[3-(3-methyl-4-oxo-9-propionyl-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

[0900] To a solution of Example 598 (0.05 g, 0.011 mmol) in toluene (2ml) under N₂ was added thionyl chloride (1 ml) and heated at reflux for3 h. The solution was concentrated using toluene to azeotrope. To asolution of diethylzinc (1 ml, 1 mmol) under N₂ stirring at −20° C. wasadded a solution of CuCN (0.093 g, 1.04 mmol) and LiCl (0.086 g, 2.02mmol) in THF (1.5 ml). This mixture was gradually allowed to warm to 0°C., stirred for 15 min at this temperature, and cooled to −25° C. Tothis solution was added the acid chloride residue in THF (0.5 ml) andstirred for 1.5 h gradually allowing to warm to 0° C. The reaction wasdiluted with NH₄Cl(aq) and extracted with dichloromethane (2×). Thecombined organic layers were washed (brine), dried (MgSO₄), filtered,and concentrated. Column chromatography (silica gel,acetone/dichloromethane gradient) gave the title compound (0.013 g, 28%o). MS(ES+) (m/z) 472.2 [M+1].

Example 610 & 6115-[3-(2-Benzenesulfinyl-ethyl)-cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one&5-[3-(2-Benzenesulfonyl-ethyl)-cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0901] A compound from Example 501 (0.20 g, 0.00044 mol) was dissolvedin CH₂Cl₂ (30 mL) and the mixture cooled under a nitrogen atmosphere inan ice bath. Then 3-chloroperoxy-benzoic acid (50%, 0.15 g, 0.00044 mol)was added and the mixture stirred for 6 h while warming to ambienttemperature. The mixture was quenched with aq NaHCO₃ and extracted withCH₂Cl₂. The combined extracts were dried over sodium sulfate andconcentrated in vacuo. The resulting residue was chromatographed oversilica gel using CH₂Cl₂/THF as eluent which allowed for isolation ofboth the pure sulfoxide (0.075 g, 36%), MS(ES): (M+1)⁺ 469.1, 471.2 m/z,and pure sulfone (0.025 g, 12%). MS(ES): (M+1)⁺ 485.4, 487.3 m/z.

Example 6125-(3-Aminomethyl-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one(d,l)

[0902] To 41.5 mg (0.093 mmol) of Example 507 was added 0.75 mltrifluoroacetic acid. After 10 nm stirring at rt, starting material (viaTLC) was consumed. The crude reaction mixture was diluted with EtOAc andsat'd aq. bicarbonate and transferred to a sep funnel. The aqueous phasewas reextracted two add'l times with EtOAc, and the combined organicswere washed with brine, dried over Na₂SO₄, filtered and concentrated toafford clean amine (28 mg, 87%) which was used without furtherpurification. MS (+ES) m/z 345.9 (M+H)⁺.

Example 613(1R,3S5-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

[0903] The product from Example 562 (0.069 g, 0.16 mmol) was treatedwith TFA (2 mL) and stirred at room temperature for 15 min. The reactionwas added dropwise to sat HCO₃ ⁻ (10 mL) and the product was extractedwith CH₂Cl₂ (5×10 mL). The solvent was removed in vacuo to afford 0.05 g(94%) of the title compound as a white solid. MS (ES+) m/z 346.0 (M+H)⁺.

Example 614(1S,3R)-5-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

[0904] The product of Example 553 (0.08 g, 0.18 mmol) was treated withTFA (2 mL) and stirred at room temperature for 20 min. The reaction wasadded dropwise to sat HCO₃ ⁻ (10 mL) and the product was extracted withCH₂Cl₂ (5×10 mL). The solvent was removed in vacuo to afford 0.047 g(76%) of title compound as a white solid. MS (ES+) m/z 346.0 (M+H)⁺.

Example 615(1R,3S)-5-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

[0905] A solution of the product from Example 508 (0.40 g, 0.83 mmol) indry CH₂Cl₂ (5 mL) was treated with iodotrimethylsilane (0.25 g, 1.25mmol) and stirred at r.t. After 3 hr the reaction was quenched with MeOH(2 mL) and stirred for an additional 30 min. The solution was thenconcentrated to an orange solid and taken up in EtOAc (20 mL) and 1 NHCl (20 mL) and transferred to a sep funnel. The organic layer wasextracted and the aqueous layer was washed with additional EtOAc (2×10mL). The pH of the aqueous layer was then adjusted to ph˜12 with 5 MNaOH. The product was extracted with EtOAc (3×25 mL). The EtOAcextractions were dried over sodium sulfate, filtered, and the solventremoved in vacuo to afford 0.240 g (84%) as a white solid which was usedwithout further purification. MS (ES+) m/z 346.0 (M+H)⁺.

Example 6165-(3-Aminomethylcyclohexyl)₉-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

[0906] The product from Example 560 (30 mg, 0.067 mmol) was treated withHCl-1.0 M in HOAc (2 mL). The reaction was stirred at r.t. for 20minutes. Acetonitrile (2 mL) was added and the solution was concentratedto a white solid. The white solid was suspended in ether and filtered toafford 15 mg (70%) as a white solid. MS S+) m/z 346.0 (M+H)⁺.

Example 6175-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,5-c]quinolin-4-one

[0907] The product of Example 561 (30 mg, 0.067 mmol) was treated withHCl-1.0 M in HOAc (2 mL). The reaction was stirred at r.t. for 20minutes. Acetonitrile (2 mL) was added and the solution was concentratedto a white solid. The white solid was suspended in ether and filtered toafford 13 mg (60%) as a white solid. MS (ES+) m/z 346.0 (M+H)⁺.

Example 6183-[2-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexyl]-N-(3,4,5-trimethoxyphenyl)propionamide

[0908] The amide from preparation 165 (24 mg, 0.042 mmol) was dissolvedin anhydrous DMF (0.5 ml). NaHMDS (1 M in THF, 0.046 ml, 1.1 eq) wasadded dropwise. After 1 hr, sm still present, and additional base (1.1eq) was added, followed by a third volume (1.1 eq) an hour later. Thereaction was then allowed to proceed o.n. The reaction was then quenchedwith 0.1 N HCl and EtOAc, transferred to a sep funnel, and the aqueousphase was reextracted two additional times, the combined organics werewashed with sat'd bicarbonate, then with brine, dried over Na₂SO₄,filtered and concentrated to afford 21 mg of crude product. Purificationover silica (1 g Bond-Elut cartridge, 2:1 EtOAc/hexanes) afforded 21 mgof product (40%). MS (+ES) 553.9, 555.9 (M+H)⁺.

Example 6195-(3-Aminomethylcyclopentyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0909] A mixture of Example 518 (240 mg, 0.5 mmol) and trimethyl silyliodide (154, 077 mmol) dissolved in methylene chloride (10 mL) wasstirred overnight at rt The reaction mixture was passed through BondElut SCX column (20 cc, 5 g), eluted with ammonia solution in methanol(1M, 20 mL) and evaporated to obtain the title compound (150 mg, 90%).ESMS: 332 (M+1)⁺.

Example 6205-[((1R,3S3-Aminocyclopentyl)methyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0910]N-{(1S,3R)-3-[(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))methyl]cyclopentyl}(tert-butoxy)carboxamidewas converted to the amine by TFA in DCM at rt. for three hours. ESMS:332 (M+1)+.

Example 6215-[((1S,3R)-3-Aminocyclopentyl)methyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0911]N-{(1R,3S)-3-[(9-chloro-3-methyl-4-oxo-5H-isoxazolo-[4,3-c]quinolin-5-yl))methyl]cyclopentyl}(tert-butoxy)carboxamidewas converted to the amine as described in Example 620. ESMS: 332(M+1)+.

Example 622cis-1-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-phenyluriedo)-cyclohexane

[0912] To the suspension ofcis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)₃-amino-cyclohexane(0.0446 g, 0.121 mmol) in 1 mL anhydrous THF at RT was added 2N NaOH(0.60 mL, 0.121 mmol). After 5 min. the phenylisocyanate (0.013 mL,0.121 mmol). After 20 min. the reaction was diluted with EtOAc, washedwith water and concentrated to near dryness. After sonication andfiltration a white solid (0.0412, 75%) was obtained. ESIMS m/e 451 ³⁵Cl(M⁺+1) and 453 ³⁷Cl (M⁺+1).

Example 623cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-[3-(phenylmethyl)uriedo]cyclohexane

[0913] A procedure similar to that for Example 622 was used to preparethe title compound as a yellow solid (0.110 g, 87%). ESIMS rte 465 ³⁵Cl(M⁺+1) and 467 ³⁷Cl (M⁺+1).

Example 624cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-cyclohexyluriedo)cyclohexane

[0914] A procedure similar to that for Example 622 was used to preparethe title compound as a yellow solid (0.106 g, 86%). ESIMS m/e 457·³¹Cl(M⁺+1) and 459 ³⁷C1 (M⁺+1).

Example 625 Preparation of racemiccis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-ethyluriedo)cyclohexane

[0915] A procedure similar to that for Example 622 was used to preparethe title compound as a yellow solid (0.102 g, 94%). ESIMS m/e 403 ³⁵Cl(M⁺+1) and 405 ³⁷Cl (M⁺+1).

Example 626cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-propyluriedo)cyclohexane

[0916] A procedure similar to that for Example 622 was used to preparethe title compound as a yellow solid (0.106 g, 94%). ESIMS m/e 417 ³⁵C1(M⁺+1) and 419 ³⁷Cl (M⁺+1).

Example 627(1S,3R)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-[((2S)-2-amino-2-phenylacetyl)amino]cyclohexanehydrochloride

[0917] To the product from Example 11 (0.015 g, 0.027 mmol) in 1 mLCH₂Cl₂ was added 1 mL 4M HCl in dioxane. After 3 h the mixture wasstripped to dryness to give the title compound as a white solid (0.0131g, 98%). ESIMS m/e 465 ³⁵Cl (M⁺+1) and 467 ³⁷Cl (M⁺+1).

Example 628(1R,3S)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-[((2S)-2-amino-2-phenylacetyl)amino]cyclohexanehydrochloride

[0918] To the product from Example 11 (0.013 g, 0.023 mmol) in 1 mLCH₂Cl₂ was added 1 mL 4M HCl in dioxane. After 3 h the mixture wasstripped to dryness to give, a white solid (0.0115 g, 100%). ESIMS m/e465 ³⁵Cl (M⁺+1) and 467 ³⁷Cl (M⁺+1).

Example 629(1S,3R)-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-[((2R)-2-amino-2-phenylacetyl)amino]cyclohexane hydrochloride

[0919] To the product from Example 11 (0.013 g, 0.019 mmol) in 1 mLCH₂Cl₂ was added 1 mL 4M HCl in dioxane. After 3 h the mixture wasstripped to dryness to give a white solid (0.0098 g, 100%). ESIMS m/e465 ³⁵Cl (M⁺+1) and 467 ³⁷Cl (M⁺+1).

Examples 630 and 631N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-(5-methyltetrazol-2-yl)-2-phenylacetamide&N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-(5-methyltetrazol-1-yl)-2-phenylacetamide

[0920] To a 0° C. solution ofN-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-2-phenyl(30 mg, 0.06 mmol) in toluene (4 mL) was added triphenylphosphine (20mg, 0.08 mmol), 5-methyltetrazole (8 mg, 0.10 mmol), anddiethylazodicarboxylate (16 μL, 0.10 mmol) dropwise. After 30 minutesthe reaction was allowed to warm to room temperature overnight.Purification gave 4.4 mg and 10.2 mg, respectively as white solids, 43%combined yield. ¹H NMR: consistent with structures. MS (ion spray) 532(M⁺).

Example 6325-(3-Aminomethylcyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydroiodide

[0921] To a 0° C. solution of[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-carbamicacid be (5.0 g, 10.4 mmol) in dichloromethane (100 mL) was addediodotrimethylsilane (3.6 mL, 25.0 mmol) dropwise, and the solutionallowed to warm to room temperature overnight. Methanol (6.1 mL, 150.0mmol) was added dropwise over two minutes, and the reaction stirred for30 minutes. The reaction was concentrated and suspended in ethyl ether.After 15 minutes of sonication, the solids were removed by filtrationand washed with ethyl ether. The tan powder was dried on a vacuum pumpto give 4.61 g as the 1.2 HI salt, 89% yield. ¹H NM: consistent withstructure. MS (ion spray) 346 (M⁺).

Example 6332-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenylacetamide

[0922] A compound from Example 235 (180 mg, 0.32 mmol) was combined withtrifluoroacetic acid (0.75 mL) in dichloromethane (4.0 mL) and themixture stirred at ambient temperature until deprotection was complete.The mixture was then concentrated in vacuo and the residue treated withaqueous NaHCO₃ and extracted with ethyl acetate. Concentration left aresidue, which was chromatographed over silica(methanol/dichloro-methane) allowing for isolation of the desiredproduct (145 mg, 97%) as a white solid. MS(ES): (M+1)⁺ 465.2, 467.2 m/z.

Example 6345-(3-Aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydroiodide

[0923] To a solution of(3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]carbamicacid methyl ester, 2.0 g (5.1 mmol) in 50 mL of dichloromethane wasadded 1.74 mL (12.2 mmol) of trimethylsilyliodide. The reaction mixturewas stirred overnight at ambient temperature and was quenched dropwisewith 3.0 mL (73.4 mmol) of methanol. The mixture was stirred 30 minutesat ambient temperature and was concentrated to dryness. The residue wastriturated with ether, filtered and dried to provide a quantitativeyield of the desired isomer as a tan solid. ¹H-NMR is consistent withstructure. MS (ion spray) 332.1 (M+for free base).

Example 635 Pyridazine-4-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]amide

[0924] 4-Methylpyridazine, 4.0 mL (44.6 mmol) was dissolved in 200 mL ofwater and 16.2 g (103 mmol) of potassium permanganate was added. Theresulting slurry was refluxed for 30 min, then an additional 8.5 g (54mmol) of potassium permanganate was added. The resulting slurry wasrefluxed for 24 h, then filtered hot through celite. The resultingsolution was washed with ether, acidified to pH=7 with 5 N HCl, andconcentrated to a volume of 80 mL. This solution was acidified to pH=2with 1 N HCl and extracted with ethyl acetate and with 20%isopropanol/chloroform. The combined organics were dried over sodiumsulfate, filtered and concentrated to dryness to yield 320 mg of a tanfoam. ¹H NMR indicated a 2:1 mixture of 4-pyridazine carboxylic acid:starting material 4-methylpyridazine.

[0925] This mixture, 40 mg, was added to a solution of 66 mg (0.14 mmol)of a compound from Example 632 in 5 mL of N,N-dimethylformamide. To thissolution was added 23 mg (0.17 mmol) of 1-hydroxy-7-azabenzotriazole, 33mg (0.17 mmol) of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimidehydrochloride, 5 mg of 4-dimethylaminopyridine and 60 μL (0.42 mmol) oftriethylamine. Yield=33 mg (53%) of the desired isomer as a white foam.¹H-NMR is consistent with structure. MS (ion spray) 452.2 (M+).

Example 636 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amidehydrochloride

[0926] A solution of3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester, 74 mg (0.125 mmol) in 5 mL of acetic acid saturatedwith HCl gas was stirred for three hours at ambient temperature, thenwas concentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness to give a quantitative yield of the desiredisomer as a white solid. ¹H-NMR is consistent with structure. MS (ionspray) 491.0 (M+).

Example 637 1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amidehydrochloride

[0927] A solution of3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, 74 mg (0.125 mmol) in 5 mL of acetic acidsaturated with HCl gas was stirred for four hours at ambienttemperature, then was concentrated to dryness. The residue was slurried3× in toluene and concentrated to dryness to give a quantitative yieldof the desired isomer as a white solid. ¹H-NMR is consistent withstructure. MS (ion spray) 491.3 (M+).

Example 6382-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenylacetamide

[0928]{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-carbamicacid tert-butyl ester (1.24 g; 2.2 mmol) was dissolved in excess, neatacetic acid saturated with HCl_((g)) (20 mL). After stirring 30 min atroom temperature, the solution was concentrated to dryness by rotaryevaporation. Acetic acid was removed from the resulting solid byconsecutive dissolution in, and drying from, acetonitrile (thrice) andthen diethyl ether (once). The solid was dissolved in 25% (v/v)isopropyl alcohol in chloroform, washed with saturated NaHCO_(3(aq)),and dried by rotary evaporation to yield the desired product in 97%isolated yield.

[0929] MS(ES) calc'd: [M+H]⁺=465.2 in/z. Found: 465.2 m/z.

Example 6392-Amino-N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenylmethyl}-2-methylpropionamidehydrochloride

[0930] A compound from Example 321 was deprotected in a manner similarto Example 638 and kept as the hydrochloride salt. MS(ES) calc'd:[M+H]⁺=550.2 m/z; [M−H]⁻=548.2 m/z; [M+Cl]⁻=584.2 m/z. Found: 550.0 m/z;548.0 m/z; 584.0 m/z.

Example 6402-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-pyridin-3-ylacetamide

[0931] A compound from Example 326 was deprotected in a manner similarto Example 638. The free base was separated into individualdiastereomers by radial chromatography on a 2 mm thick silica gel rotorwith a 2% methanol/dichloromethane (v/v) mobile phase (300 mL) followedby increasing methanol to 10% in step gradients (each mobile phase nowcontaining 1% triethylamine). The desired product was isolated as 13 mgof isomer 1, 18 mg of isomer 2, and 7 mg mixed product. Isomer 1 MS(ES)exact mass calc'd: [M+H]⁺=466.1646 m/z. Found: 466.1648 m/z. Isomer 2MS(ES) exact mass calc'd: [M+H]⁺=466.1646 m/z. Found: 466.1663 m/z.

Example 641N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl]-thiobenzamide

[0932] A solution of cis-N-1[39-chloro-3-methyl-4-oxo-SH-isoxazolo[4,5-c]quinolin-5-yl))cyclohexyl]methyl}benzamide(0.1 g, 0.2 mmol) in pyridine (10 mL) was treated with P₂S₅ (0.37 g, 1.7mmol) and heated to reflux. The reaction was stirred for 1 hour atreflux and then allowed to cool to r.t. The reaction was quenched withwater (150 mL) A white precipitate formed and was filtered to afford alight yellow solid. This solid was taken up in CH₂Cl₂ (15 mL) andpurified by silica gel column chromatography. The product was elutedwith 1% MeOH in CH₂Cl₂. The solvent was removed to afford 0.082 g (81%)of a yellow solid. MS m/z (ES+) 465.8 (M+H)⁺, (ES−) 463.8 (M−H)⁻.

Example 642N-[3-(9-Chloro-3-methyl-4-oxo-2,4-dihydropyrazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

[0933]cis-N-({3-[3-(aminoethylidene)-5-chloro-2,4-dioxohydroquinolyl]-cyclohexyl}methyl)benzamide(0.15 g, 0.3 mmol) and hydrazine hydrate-85% (0.016 g, 0.49 mmol) inEtOH (20 mL). The reaction was heated to reflux and stirred for 6 hr.The reaction was then concentrated to a solid and taken up in CH₂Cl₂.This solution was purified by silica gel column chromatography using 50%EtOAc in CH₂Cl₂ to elute the product. The solvent was removed to afford0.095 g (64%) as a yellow solid. MS (ES+) m/z 448.9 (M+H)⁺, (ES−) m/z446.9 (M−H)⁻, 506.9 (M+CH3COO⁻)⁻.

Example 643N-[3-(9-Chloro-3-methyl-4-oxo-2,4-dihydropyrazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-6-fluoronicotinamide

[0934]cis-N-({3-[3-(Aminoethylidene)-5-chloro-2,4dioxohydroquinolyl]-cyclohexyl}methyl)(6-fluoro(3-pyridyl))carboxamide(0.92 g, 0.2 mmol) and hydrazine hydrate-85% (0.063 g, 0.3 mmol) in EtOH(20 mL). The reaction was heated to reflux and stirred for 1 hr. Thereaction was then concentrated to a solid and taken up in CHCl₃. Thissolution was purified by silica gel column chromatography using 5% MeOHin CHCl₃ to elute the product. The solvent was removed to afford 0.02 g(22%) as a white solid MS (ES+) m/z 468.1 (M+H)⁺, (ES−) m/z 466.1(M−H)⁻, 526.2 (M+CH3COO⁻)⁻.

Example 644[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl]-carbamicacid benzyl ester

[0935] A solution ofN-{[3-(3-acetylamino-5-chloro-2-oxohydroquinolyl)-cyclobexyl]-methyl}(phenylmethoxy)carboxamide(0.02 g, 0.04 mmol) in acetic acid (2 mL) was treated with hydroxylaminehydrochloride (3 mg, 0.046 mmol). The solution was heated to reflux andstirred 4 hr. The reaction was then diluted in CH₂Cl₂ (50 mL) and washedwith 5M NaOH (3×10 mL) and brine (2×10 mL). The organic was dried oversodium sulfate and the solvent removed. The crude product was purifiedby silica gel column chromatography using 10% EtOAc in CH₂Cl₂ to elutethe product. The solvent was removed iii vacuo to afford 0.014 g (70%)of the title compound as an off-white solid.

[0936] MS (ES+) m/z 500.1 (M+H)⁺.

Example 645N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl]-6-fluoronicotinamide

[0937] A solution ofN-{[3-(3-acetylamino-5-chloro-2-oxohydroquinolyl)cyclohexyl]-methyl}(6-fluoro(3-pyridyl))carboxamide(0.035 g, 0.07 mmol) in acetic acid (5 mL) was treated withhydroxylamine hydrochloride (7.8 mg, 0.11 mmol). The solution was heatedto reflux and stirred 3 hr. The reaction was then diluted in CHCl₃ (50mL) and washed with sat'd sodium bicarbonate (3×10 mL) and brine (2×10mL). The organic was dried over sodium sulfate and the solvent removed.The crude product was purified by silica gel column chromatography using50% EtOAc in CHCl₃ to elute the product. The solvent was removed invacuo to afford 0.025 g (72%) of the title compound as a white solid. MSm/z (ES+) 468.8 (M+H)⁺, (ES−) 466.8 (M−H)⁻, 526.8 (M+CH3COO⁻)⁻.

Example 646N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c)quinolin-5-yl)-cyclohexylmethyl]-4-fluoro-benzamide

[0938] To a solution of a compound from Example 524 (0.106 g, 0.23 mmol)in CH₂Cl₂ (10 ml) under N₂ was added TMSI (0.36 ml, 2.52 mmol) andstirred overnight. Added MeOH (5 ml) and stirred for 1 h to quench thereaction. The mixture was concentrated, triturated with toluene anddried to obtain a crude solid. This was mixed with 4-fluorobenoylchloride (0.093 ml, 0.8 mmol) in CH₂Cl₂ (5 ml) under N₂ andtriethylamine (0.22 ml, 1.6 mmol) was added dropwise. After stirringovernight, the mixture was diluted with CH₂Cl₂, washed (0.1N HCl thenbrine), dried (MgSO₄), filtered, and concentrated. Flash chromatography(silica gel, acetone/CH₂Cl₂ gradient) gave the title compound (0.085 g,88%). Mass Spectrum (ES+) (m/z) 459.1 [M+1].

Example 647 N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-3,4-difluorobenzamide

[0939] In a fashion similar to that described for Example 527, acompound from Example 524 (0.106 g, 0.23 mmol), CH₂Cl₂ (10 ml), TMSI(0.36 ml, 2.52 mmol), 3,4-difluorobenzoyl chloride (0.093 ml, 0.8 mmol),CH₂Cl₂ (5 ml), and triethyamine (0.22 ml, 1.6 mmol) gave the titlecompound (0.087 g, 87%) after flash chromatography (silica gel,acetone/CH₂Cl₂ gradient). Mass Spectrum (ES+) (m/z) 477.1 [M+1].

Example 648N-[3-(9-Chloro-4-oxo-3-phenylsulfanyl-5H-isoxazole[4,3-c]quinolin-5-yl)-cyclohexylmethyl]benzamide

[0940] To a solution ofN-{[3-(3-acetyl-4-amino-5-chloro-2-oxohydroquinoly])-cyclohexyl]methyl}(6-fluoro(3-pyridyl))carboxamide(0.1 g, 0.2 mmol) in DMF (2.5 ml) under N₂ was added sodiumthiophenoxide (0.132 g, 1.0 mmol) and stirred for 2 h. The reaction wasdiluted with EtOAc, washed (H₂O then brine), dried (MgSO₄), filtered,and concentrated. The residue was dissolved in DMF (2 ml) under N₂,cooled to 0 degrees C., and KHMDS (0.566 ml, 0.28 mmol) was added over15 min. After 30 min, the solution was diluted with EtOAc, washed (H₂Oand brine), dried (MgSO₄), filtered, and concentrated. Flashchromatography (silica gel, Acetone/CH₂Cl₂ gradient) gave the titlecompound (0.045 g, 41%). Mass Spectrum (ES+) (m/z) 544.2 [M+1].

Example 649N-[3-(9-Chloro-3-ethoxy-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-benzamide

[0941] To a solution of 278 (0.1 g, 0.2 mmol) in DMF (2.5 ml) under N₂was added sodium ethoxide (0.33 ml at 21% wt., 1.0 mmol) and stiffed for2 h. The reaction was diluted with EtOAc, washed (H₂O then brine), dried(MgSO₄), filtered, and concentrated. Purification by flashchromatography gave the title compound (0.025 g, 26%) (silica gel,acetone/CH₂Cl₂ gradient). Mass Spectrum (ES+) (m/z) 480.2 [M+1].

Example 650N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-methylamino-acetamidehydrochloride

[0942] A solution of the compound from Example 333, 66 mg (0.13 mmol) in10 mL of HCl-saturated acetic acid was stirred 4 hours at rt., thenconcentrated to dryness., The residue was slurried 3× in toluene andconcentrated to dryness to give a quantitative yield of the desiredisomer as a white foam. ¹H-NMR is consistent with structure. MS (ionspray) 403.2 (M+).

Example 6512-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-methyl-propionamidehydrochloride

[0943] A solution of the compound from Example 335, 64 mg (0.12 mmol) in10 mL of HCl-saturated acetic acid was stirred 3 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredisomer as a white foam. MS (ion spray) 417.1 (M+).

Example 6522-Amino-N-[3-(9-chloro-3-methyl-4-oxo-SH-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-acetamidehydrochloride

[0944] A solution of the compound from Example 336, 49 mg (0.10 mmol) in10 mL of HCl-saturated acetic acid was stirred 3 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredisomer as a tan foam. MS (ion spray) 389.1 (M+).

Example 653N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenyl-2-piperazin-1-ylacetamidedihydrochloride

[0945] A solution of the compound from Example 339, 171 mg (0.27 mmol)in 10 mL of HCl-saturated acetic acid was stirred 2 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredmixture of isomers as a tan foam. ¹H-NMR is consistent with structure.MS (ion spray) 389.1 (M+). The isomers were separated by chiralchromatography in a similar fashion to that described for Example 554 toyield 31.5 mg (19%) of isomer 1 as a white foam and 32.9 mg (209%) ofisomer 2 as a white foam. I.S. (534.2) M+.

Example 654N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-methylamino-2-phenylacetamidehydrochloride

[0946] A solution of the compound from Example 340, 130 mg (0.22 mmol)in 10 mL of HCl-saturated acetic acid was stirred 2 hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to give a quantitative yield of the desiredmixture of isomers as a white foam. MS (ion spray) 479.2 (M+).

Example 655 1-Aminocyclohexanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amidehydrochloride

[0947] A solution of the compound from preparation 229a, 198 mg (0.35mmol) in 15 mL of HCl-saturated acetic acid was stirred three hours atrt. then concentrated to dryness. The residue was slurried 3× inacetonitrile and concentrated to dryness to give 160 mg (93%) of thedesired isomer as a white solid. MS (ion spray) 457.2 (M+1).

Example 6562-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-cyclohexylacetamidehydrochloride

[0948] A solution of the compound from Example 355, 80 mg (0.14 mmol) in30 mL of HCl-saturated acetic acid was stirred four hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness to give 60 mg (85%) of the desired isomer as atan solid. MS (ion spray) 471.2 (M+).

Example 6572-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-cyclohexylacetamidehydrochloride

[0949] A solution of the compound from Example 356, 100 mg (0.17 mmol)in 30 mL of HCl-saturated acetic acid was stirred four hours at rt. thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness to give 47 mg (55%) of the desired isomer as atan solid. ¹H-NMR is consistent with structure. MS (ion spray) 471.2(M+).

Example 658 2-Aminoindan-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]amidehydrochloride

[0950] A solution of a compound from Example 634, 220 mg (0.37 mmol) in40 mL of HCl-saturated acetic acid was stirred three hours at rt, thenconcentrated to dryness. The residue was slurried 3× in toluene andconcentrated to dryness give a quantitative yield of the desired isomeras a white solid. MS (ion spray) 491.2 (M+).

Example 6592-Amino-N-[3-(9-chloro-3-methyl-4-oxo-SH-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-3-phenylpropionamide

[0951] A solution of the compound from Example 370, 84 mg (0.14 mmol) in10 mL of HCl-saturated acetic acid was stirred four hours at rt., thenconcentrated to dryness. The residue was slurried 3× in acetonitrile andconcentrated to dryness give a quantitative yield of the desired isomeras a tan foam. MS (ion spray) 479.1 (M+).

Example 6605-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0952] A compound from Example 634 (350 mg, 0.95 mmol) was treated withexcess aqueous NaHCO₃ and the mixture extracted with EtOAc. The combinedextracts were dried over Na₂SO₄ and concentrated in vacuo to yield 309mg (98%) of the title compound.

Example 661N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-4-fluorobenzamide

[0953] To a solution of a compound from Example 532 (0.106 g, 0.23 mmol)in CH₂Cl₂ (2 mL) under N₂ was added TMSI (0.046 mL, 0.32 mmol) andstirred overnight. Added MeOH (1 mL) and stirred for 1 h to quench thereaction. The mixture was concentrated, triturated with toluene anddried to obtain a crude solid. This was mixed with 4-fluorobenoylchloride (0.093 mL, 0.8 mmol) in CH₂Cl₂ (5 mL) under N₂ and Et₃N (0.22mL, 1.6 mmol) was added dropwise. After stirring overnight, the mixturewas diluted with CH₂Cl₂, washed (0.1N HCl then brine), dried (MgSO₄),filtered, and concentrated. Flash chromatography (silica gel,Acetone/CH₂Cl₂ gradient) gave the title compound (0.085 g, 88%). MassSpectrum (ES+) (m/z) 459.1 [M+1].

Example 662N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-3,4-difluorobenzamide

[0954] In a fashion similar to that described for Example 542, acompound from Example 413 (0.1 g, 0.21 mmol), CH₂Cl₂ (2 mL), TMSI (0.046mL, 0.32 mmol), 3,4-difluorobenoyl chloride (0.093 mL, 0.8 mmol), CH₂Cl₂(5 mL), and Et₃N (0.22 mL, 1.6 mmol) gave the title compound (0.087 g,87%) after flash chromatography (silica gel, acetone/CH₂Cl₂ gradient).Mass Spectrum (ES+) (m/z) 477.1 [M+1].

Example 663N-[3-(9-Chloro-3-ethoxy-4-oxo-5H-isoxazole[4,3-c]quinolin-5-yl)cyclohexylmethyl]-benzamide

[0955] To a solution of a compound from preparation 328 (0.1 g, 0.2mmol) in DMF (2.5 mL) under N₂ was added sodium ethoxide (0.33 mL at 21%wt., 1.0 mmol) and stirred for 2 h. The reaction was diluted with EtOAc,washed (H₂O then brine), dried (MgSO₄), filtered, and concentrated.Purification by flash chromatography gave the title compound (0.025 g,26%) (silica gel, acetone/CH₂Cl₂ gradient). Mass Spectrum (ES+) (m/z)480.2 [M+1].

Example 664N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-6-fluoronicotinamide

[0956] To a solution ofN-{[3-(9-cyano-3-methyl-4-oxo(5-hydroisoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}(phenylmethoxy)carboxamide(0.27 g, 0.58 mmol) in CH₂Cl₂ (7 mL) under N₂ was added TMSI (0.2 mL,1.4 mmol) and stirred overnight. Added MeOH (3 mL) and stirred for 1 hto quench the reaction. The mixture was concentrated, triturated withtoluene and dried to obtain a crude solid. This was mixed with6-fluoronicontic acid (0.114 g, 0.81 mmol) in DMF (5 mL) under N₂ and tothis solution was added EDCI (0.16 g, 0.81 mmol) and DMAP (0.131 g, 1.08mmol). After stirring overnight, the mixture was diluted with EtOAc,washed (120 then brine), dried (MgSO₄), filtered, and concentrated.Flash chromatography (silica gel, Acetone/CH₂Cl₂ gradient) gave thetitle compound (0.198 g, 80%). Mass Spectrum (ES+) (m/z) 460.3 [M+1].

Example 6656-Chloro-N-[3-(9-cyano-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]nicotinamide

[0957] In a fashion similar to that described for Example 664, acompound from Example 532 (0.1 g, 0.21 mmol), CH₂Cl₂ (2 mL), TMSI (0.046mL, 0.32 mmol), 6-chloronicotinic acid (0.068 g, 0.43 mmol), DMF (4 mL),EDCI (0.62 g, 0.32 mmol) and DMAP (0.052 g, 0.43 mmol) gave the titlecompound (0.045 g, 44%) after flash chromatography (silica gel,EtOAc/Hexanes gradient). Mass Spectrum (ES+) (m/z) 476.2 [M+1].

Example 666N-[3-(9-Cyano-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-6-methylnicotinamide

[0958] In a fashion similar to that described for Example 664, acompound from Example 532 (0.1 g, 0.21 mmol), CH₂Cl₂ (2 mL), TMSI (0.046mL, 0.32 mmol), & methyl-nicotinic acid (0.059 g, 0.43 mmol), DMF (4mL), EDCI (0.62 g, 0.32 mmol) and DMAP (0.131 g, 1.08 mmol) gave thetitle compound (0.045 g, 44%) after flash chromatography (silica gel,EtOAc/Hexanes gradient). Mass Spectrum (ES+) (m/z) 456.2 [M+1].

Example 667N-[3-(9-Amino-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl]-benzamide

[0959] To a solution of a compound from preparation 333 (0.24 g, 0.42mmol) in THF (4.2 mL) under N₂ was added TBAF (0.84 mL, 0.84 mmol, 1.0Min THF) dropwise and stirred for 4 h. The reaction was applied directlyto a silica gel column and eluted with EtOAc which gave the titlecompound (0.18 g, 99%). Mass Spectrum (ES−) (m/z) 429.3 [M−1]

Examples 668 & 6699-Chloro-5-[3-(2-hydroxy-2-phenylethylamino)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one&9-Chloro-5-[3-(2-hydroxy-1-phenylethylamino)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0960] To a stirred solution of a compound from Example 634 (440 mg,1.33 mmol) in abs. EtOH (60 mL) was added S-styrene oxide (159.2 mg,1.33 mmole) under N₂ atmosphere. The reaction mixture was refluxed for22 h. The solvent was removed on Buchi and the crude was chromatographedby Elution solution systems (40L column, NH₃ in MeOH: EtOAc, gradient).The title compounds were yielded (A, 201 mg; B, 41 mg, 40.3% yield).Mass Spectrum(FIA); A(m/z) 452.2 (M+1); B(m/z) 452.2 (M+1).

Examples 670 & 6719-Chloro-5-[3-(2-hydroxy-2-phenylethylamino)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one&9-Chloro-5-[3-(2-hydroxy-1-phenylethylamino)cyclohexyl]-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0961] To a stirred solution of a compound from Example 634 (441 mg,1.33 mmole) in abs. EtOH (60 mL) was added R-styrene oxide (160 mg, 1.33mmole) under N₂ atmosphere. The reaction mixture was refluxed for 202 h.The solvent was removed on Buchi and the crude was chromatographed byElution solution systems (40L column, NH₃ in MeOH: EtOAc, gradient). Thetitle compounds were yielded (A, 161 mg; B, 40 mg, 33.4% yield). MassSpectrum (FIA) A(m/z) 452.2 (M+1); B(m/z) 452.2 (M+1).

Example 6729-Chloro-3-methyl-5-[3-(2-oxo-5-phenyloxazolidin-3-yl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

[0962] To a stirred solution of a compound from Example 668 (41 mg,0.091 mmole) in THF (2 mL) was added DCC (15 mg, 0.091 mmole) and Et₃N(0.013 mL, 0.091 mmole). The reaction mixture was stirred at rt under N₂atmosphere for 18 h. It was diluted with EtOAc, washed with brine, driedover Na₂SO₄ and concentrated. The resulted crude oil was chromatographed(gradient, hexanes: EtOAc) and the desired product was yielded as whitefoam solid (23 g, 54%). Mass Spectrum: m/z calcd. 478.1533, Found478.1544

Example 6739-Chloro-3-methyl-5-[3-(2-oxo-5-phenyloxazolidin-3-yl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

[0963] To a stirred solution of a compound from Example 670 (50 mg, 0.11mmol) in THF (2 mL) was added DCC (18 mg, 0.11 mmol), Et₃N (0.016 mL,0.11 mmol) and DMAP (catalytic amount). The reaction mixture was stirredat rt. under N₂-atmosphere for 48 h. It was diluted with EtOAc, washedwith brine, dried over Na₂SO₄ and concentrated. The resulted crude oilwas chromatographed (gradient, hexanes: EtOAc) and the desired productwas yielded as white foam solid (21 g, 40%). Mass Spectrum: m/z calcd.478.1533, Found 478.1565.

Example 6749-Chloro-3-methyl-5-[3-(2-oxo-4-phenyloxazolidin-3-yl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

[0964] To a stirred solution of a compound from Example 669 (97 mg, 0.21mmole) in THF (4 mL) was added DCC (34.1 mg, 0.21 mmole), Et₃N (0.03 mL,0.21 mmole) and DMAP (catalytic amount). The reaction mixture wasstirred at rt. under N₂ atmosphere for 18 h. It was diluted with EtOAc,washed with brine, dried over Na₂SO₄ and concentrated. The resultedcrude oil was chromatographed (gradient, hexanes: EtOAc) and the desiredproduct was yielded as white foam solid (40 g, 40%). MassSpectrum(FIA)(m/z) 478.1 (M+1).

Example 6759-Chloro-3-methyl-5-[3-(2-oxo-4-phenyloxazolidin-3-yl)cyclohexyl]-5H-isoxazolo[4,3-c]quinolin-4-one

[0965] To a stirred solution of a compound from Example 671 (64 mg, 0.14mmole) in CH₂Cl₂ (5 mL) was added DCC (115 mg, 0.7 mmole), Et₃N (0.02mL, 0.14 mmole) and DMAP (catalytic amount). The reaction mixture wasstirred at rt. under N₂ atmosphere for 48 h. It was diluted with CH₂Cl₂,washed with brine, dried over Na₂SO₄ and concentrated. The resultedcrude oil was chromatographed (gradient, hexanes: EtOAc) and the desiredproduct was yielded as white foam solid (51 g, 76%). Mass Spectrum (FIA)(m/z) 478.0 (M+1).

Example 6769-Chloro-5-{3-[2-(6-chloropyridin-3-yl)-2-hydroxyethylamino]cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0966] To a stirred solution of 6-chloronicotinic acid (900 mg, 5.7mmol) in THF (7 mL) was added BH₃ (16 mL, 17.1 mmol, 1M in THF) under N₂atmosphere. The reaction mixture was stirred for 5 h. It was quenchedwith methanol (5 mL) and then concentrated. The crude was dissolved inEtOAc (30 mL), washed with 1N NaOH (15 mL×3), brine, dried andconcentrated. Yield: 615 mg (75%) of 6-chloro-pyridin-3-yl-methanol. Tothis alcohol (615 mg, 4.28 mmol) solution in CH₂Cl₂ (8 mL) was addedDess-Martin reagent (5.4 mg, 12.8 mmol). It was stirred at rt. for 2 hand then diluted with CH₂Cl₂ The resulting solution was washed with NaOH(1N, 2×5 mL), brine, dried and concentrated. 516 mg (85%) of yellowsolid as the desired 6-chloro-pyridine-3-carbaldehyde. To a solution ofabove aldehyde (401 mg, 2.82 mmol) in CH₂Cl₂ (10 mL) was added 50% NaOHsolution (9.3 mL), trimethylsulfonium iodide (1.15 g, 5.64 mmol) andtetrabutylammonium iodide (11 mg). It was refluxed for 48 h and pouredonto ice water. The organic layer was extracted with CH₂Cl₂, washed withbrine, dried and concentrated. The crude epoxide was chromatographed(gradient, hexanes: EtOAc) and 190 mg (43%) yellow oil was yielded asdesired 2-Chloro-5-oxiranyl-pyridine. To the solution of2-chloro-5-oxiranyl-pyridine (118.4 mg, 0.76 mmol) in absolute ethanol(40 mL) was added a compound from Example 660 (252 mg, 0.76 mmol). Thereaction mixture was refluxed for 24 h and concentrated.

Example 677[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cycloheptylmethyl]-carbamicacid 2-trimethylsilanylethyl ester

[0967] To a warm solution of 0.2 g (0.52 mmol) of a compound fromExample 680 in toluene (4 mL) was added 0.154 mL (0.72 mmol) of DPPAfollowed by 0.1 mL (0.72 mmol) of Et₃N. After heating the solution at80° C. for 2 hours, 0.11 mL (0.78 mmol) of the silyl alcohol was addedand the reaction was heated at 85° C. for 12 hours. The reaction wascooled, diluted with EtOAc, rinsed with water followed by brine, anddried over Na₂SO₄. The solvent was removed iii vacuo and the residue waschromatographed on silica gel with 2/1 hexanes/EtOAc to yield 0.127 g ofthe title compound.

[0968] MS(ES+)m/z=504.

Example 678N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)R-cycloheptylmethyl]benzamide

[0969] A solution of 0.052 g (0.2 mmol) of a compound from Example 677in THF (6 mL), and 4.5 mL of TBAF (1.0M in THF)(4.5 mmol) was heated at60° C. for 4 hours. The solution was cooled to ambient temperature andwater (2 mL) then 0.028 g of anhydrous K₂CO₃ (0.2 mmol) were addedfollowed by 0.016 g (0.11 mmol) of benzoyl chloride. The reaction wasstirred 12 hours, after which the THF was replaced with EtOAc and rinsedwith 1N HCl and dried over Na₂SO₄. The organic layer was concentrated invacuo to a residue, which was chromatographed on silica gel with 2/1hexanes/EtOAc to yield 0.011 g of the title compound. MS(ES+)m/z=464.

Example 679N-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cycloheptylmethyl]4-fluorobenzamide

[0970] In a manner similar to the preparation of Example 678, 0.052 g(0.1 mmol) of a compound from Example 678 yielded 0.012 g of the titlecompound. MS(ES+)m/z=482.

Example 680[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohepty]aceticacid

[0971] A suspension of 0.82 g (2.0 mmol) of a compound from Example 424in 1N NaOH (45 mL) and MeOH (125 mL) was stirred for 16 hrs. at ambienttemperature. The MeOH was removed in vacuo and the reaction was cooledand neutralized with 3N HCl. The acidic aqueous layer was extracted withEtOAc, rinsed with water and concentrated in vacuo at 40° C. to yield0.78 g of the title compound. MS(ES+)m/z=388.9.

Example 681[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cycloheptylmethyl]-carbamicacid methyl ester

[0972] In a manner similar to the preparation of Example 677 (except theintermediate isocyanate was trapped with MeOH instead of TMS ethanol)0.68 g (1.8 mmols) of a compound from Example 680 was converted to 0.43g of the title compound.

[0973] MS(ES+)m/z=418.1.

Example 682N-[3R-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)R-cycloheptylmethyl]benzamide

[0974] A suspension of 0.036 g (0.1 mmol) of a compound from Example632, 0.028 g (2.0 mmol) of anhydrous K₂CO₃, and 0.013 mL (1.1 mmol) ofbenzoyl chloride in 3 mL of THF/H₂O 2/1 was stirred 15 hours. Thesolvent was removed in vacuo and the residue was taken into EtOAc andrinsed with NaHCO₃ sat., 1N HCl, and brine. The organic layer was driedover anhyd. Na₂SO₄ and the solvent was removed in vacuo. The residue wascrystallized from MeOH to yield 0.28 g of the title compound.MS(ES+)m/z=464.1.

Example 6832-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-3-phenylpropionamide

[0975] A solution of{1-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-phenylethyl}-carbamicacid tert-butyl ester, 82 mg (0.14 mmol) in 15 mL of HCl-saturatedacetic acid was stirred three hours at rt., then concentrated todryness. The residue was slurried 3× in acetonitrile and concentrated todryness to give a quantitative yield of the title compound as a tanfoam. MS (ion spray) 479.2. (M+).

Example 6842-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-3-hydroxypropionamide

[0976] A solution of{1-[3-(9-Chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbanoyl]-2-hydroxy-ethyl}-carbamicacid tert-butyl ester, 73 mg (0.14 mmol) in 8 mL of 25% TFA in CH₂Cl₂was stirred rt. for three hours then concentrated to dryness. Theresidue was partitioned between 20% isopropanol/chloroform and saturatedaqueous NaHCO₃. The organics were washed with saturated NaHCO₃, washedwith brine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by radial chromatography using MeOH/chloroform aseluent and concentrated to dryness to yield 40 mg (69%) of the titlecompound as a white solid. ¹H-NMR is consistent with structure. MS (1S)419.1 (M+).

Example 6852-Amino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-3-hydroxypropionamide

[0977] A solution of{1-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-2-hydroxy-ethyl}-carbamicacid tert-butyl ester, 92.3 mg (0.18 mmol) in 8 mL of 25% TFA in CH₂Cl₂was stirred rt. for three hours then concentrated to dryness. Theresidue was partitioned between 20% isopropanol/chloroform and saturatedaqueous NaHCO₃. The organics were washed with saturated NaHCO₃, washedwith brine, dried over Na₂SO₄, filtered and concentrated to dryness. Theresidue was purified by radial chromatography using MeOH/chloroform aseluent and concentrated to dryness to yield 37 mg (50%) of the titlecompound as a white solid. MS (1S) 419.2 (M+).

Example 686N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]6-dimethylaminonicotinamide

[0978] A solution of compound from Example 245, 50 mg, (0.10 mmol) in2.0 mL (4.0 mmol) of 2N N,N-dimethylamine in THF was stirred 24H in asealed tube at 90° C. then concentrated to dryness. The residue wasdissolved in 20% isopropanol/chloroform and washed with saturatedaqueous sodium bicarbonate, washed with brine, dried over sodiumsulfate, filtered and concentrated to dryness. The residue was purifiedby radial chromatography using a methanol/chloroform gradient as eluentand was concentrated to dryness. The residue was slurried inether/hexanes and concentrated to dryness to yield 48 mg (96%) of thedesired isomer as a white foam.

[0979]¹H-NMR is consistent with structure.

[0980] MS (ion spray) 494.2 (M+).

Example 687N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-6-methylaminonicotinamide

[0981] A solution of a compound from Example 245, 50 mg, (0.10 mmol) in2.0 mL (4.0 mmol) of 2N methylamine in tetrahydrofuran was stirred 24Hin a sealed tube at 100° C. then concentrated to dryness. Somemechanical loss occurred. The residue was dissolved in 20%isopropanol/chloroform and washed with saturated aqueous sodiumbicarbonate, washed with brine, dried over sodium sulfate, filtered andconcentrated to dryness. The residue was purified by radialchromatography using a methanol/chloroform gradient as eluent and wasconcentrated to dryness. The residue was slurried in ether/hexanes andconcentrated to dryness to yield 30 mg (62%) of the desired isomer as awhite foam. MS (ion spray) 480.1 (M+).

Example 688N-[3-(9-Chloro-3-methyl-4-oxo-SH-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-(pyridin-3-yloxy)propionamide(isomers 1 & 2)

[0982] The isomers ofN-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(pyridin-3-yloxy)-propionamide(mixture of isomers, 142 mg (0.29 mmol) was separated via chiralchromatography to yield 63.5 mg of crude isomer 1 and 60.2 mg of crudeisomer 2. Isomer 1 was purified by radial chromatography(methanol/chloroform gradient) and concentrated to dryness to yield 55.7mg (39%) of the desired isomer as a tan foam. ¹H-NMR is consistent withstructure.

[0983] MS (ion spray) 481.2 M+.

[0984] Isomer 2 was purified by radial chromatography(methanol/chloroform gradient) and concentrated to dryness to yield 51.3mg (36%) of the desired isomer as a white foam.

[0985]¹H-NMR is consistent with structure.

[0986] MS (ion spray) 481.2 M+.

Example 689N-{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentyl)methyl}benzamide

[0987] In the same manner as preparation 17,N-(t-butoxycarbonyl)₂₉-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclopentylamine(0.06 g, 0.14 mmol) of was deprotected to yield 0.044 g (0.133 mmol) ofthe free amine MS(ES+)m/z=332, which was dissolved in dichloromethane(2.5 mL). To the solution was added 0.0222 mL (0.16 mmol) of Et₃Nfollowed by 0.019 mL (0.16 mmol) of benzoyl chloride. After 45 min, thesolvent was removed in vacuo, replaced with ethyl acetate and theorganic layer was rinsed with 1N HCl followed by 1N NaOH, then water.The organic layer was dried and the solvent was removed in vacuo to givea residue which was chromatographed on silica gel with ethylacetate/hexane 1:1 to yield 0.035 g of the title compound.MS(ES+)m/z=436. Cis (racemic)

Example 690 Phenylmethyl2-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]acetate

[0988] To a solution of phenylmethyl2-((1R,3S)-3-{[4-(2-chloro-6-fluorophenyl)-2-methyl(3-furyl)]carbonylamino}cyclohexyl)acetate,5.71 g (11.8 mmol) in 100 mL of N,N-dimethylformamide at ambienttemperature was added 47 mL (23.6 mmol) of 0.5 M potassiumbis(trimethylsilyl)amide in toluene dropwise. After 10 min., thereaction was quenched with saturated ammonium chloride and extractedwith ethyl acetate. The combined organics were washed with brine, driedover sodium sulfate, filtered and concentrated to dryness. The residuewas chromatographed on silica gel using ethyl acetate/hexanes as eluentto yield 3.8 g (70%) of the desired product as a green oil.

[0989]¹H-NMR is consistent with structure.

[0990] MS (ion spray) 465.2 (M+1).

Example 6915-{(1S,3S)-3-[2-(phenylamino)ethyl]cyclohexyl}-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0991]N-{(1S,3S)-3-[2-(phenylamino)ethyl]cyclohexyl}[3-(2-chloro-6-fluorophenyl)-5-methylisoxazoltyl]carboxamide(54 mg; 0.118 mmol) was dissolved in anhydrous DMF (2 mL) under a drynitrogen atmosphere at room temperature. When potassiumbis(trimethylsilyl)amide (0.5 M in toluene; 572 μL; 2.2 equiv) was addeddropwise to this solution, a clear orange color formed. After 5 min, thereaction was chilled in an ice bath, quenched with 1N HCl(aq) (10 mL),and extracted with ethyl acetate (twice). The organic layer was washedwith saturated NaCl(aq) (once), dried with Na₂SO₄(s), filtered, andconcentrated to dryness by rotary evaporation. The product was purifiedby radial chromatography on a 2 min thick silica gel rotor. Adichloromethane mobile phase was ineffective at purifying the product.Re-chromatography with a 100% hexanes mobile phase followed by a 20%ethyl acetate/hexanes (v/v) mobile phase separated product fromimpurities. After drying from diethyl ether, an off-white foam (43 mg;84%) was obtained. TOF-MS(ES) calc'd: [M+H]+=436.1792 m/z. Found:436.1797 m/z.

Example 6925-[3-(2-Aza-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-cyclohexyl]-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

[0992] To a suspension of a compound from preparation 48 (500 mg, 1.0mmol) in J water (5 mL) was added formaldehyde (0.24 mL, 3.0 mmol)dropwise, and the mixture stirred rapidly under nitrogen. After 5minutes, freshly cracked cyclopentadiene (0.41 mL, 5.0 mmol) was addeddropwise. The solution was stirred under nitrogen at rt. overnight. Thesolution was diluted with a saturated aqueous sodium bicarbonatesolution, extracted with dichloromethane (×3), and the organics driedover magnesium sulfate and concentrated. Purification by flashchromatography on silica gel (eluting with 14% methanol/chloroform/0.5%NH₄OH) gave 183.7 mg of the title compound as a white foam, 43% yield.MS (ion spray) 424

Example 693 1-Amino-cyclopentanecarboxylic acid[3-(9-chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amidehydrochloride

[0993] A compound from Example 460 (89.9 mg, 0.17 mmol) was dissolved inHCl_((g))/AcOH (5 mL, ˜3N) and stirred at rt. After 1 h, additionalHCl_((g))/AcOH (5 mL, ˜3N) was added. After 5 h, the mixture wasconcentrated, followed by azeotropic removal of water with acetonitrilein vacuo (×3). To the white solid was added diethyl ether, and themixture was sonicated, and filtered. The resulting material was dried ona vacuum pump to give 52.9 mg of the title compound as a white solid,67% yield. ¹H NMR: consistent with structure. MS (ion spray) 479 (M+).

Example 694 1-Amino-cyclopropanecarboxylic acid (3-(9-chloro-3-methyloxo-4H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide hydrochloride

[0994] A compound from Example 461 (94.3 mg, 0.18 mmol) was dissolved inHCl_((g))/AcOH (5 mL, ˜3N) and stirred at rt. After 1 h, additionalHCl_((g))/AcOH (5 mL, ˜3N) was added. After 5 h, the mixture wasconcentrated, followed by azeotropic removal of water with acetonitrilein vacuo (×3). To the white solid was added diethyl ether, and themixture was sonicated, and filtered. The resulting material was dried ona vacuum pump to give 70.2 mg of the title compound as a white solid,85% yield. ¹H NMR: consistent with structure. MS (ion spray) 451 (M).

Example 695N-[3-(4,10-Dichloro-5-oxo-5H-benzo[h][1,6]naphthyridin-6-yl)-cyclohexylmethyl]-benzamide

[0995] To 0.045 g (0.1 mmols) ofN-{[(1R,3S)-3-(3-acetyl-4-amino-5-chloro-2-oxohydroquinolyl)cyclohexyl]methyl}benzamideand 0.03 ml (0.3 mmols) of POCl₃ were dissolved in DMF (2 ml) at 0-5° C.The reaction was allowed to warm to rt. and stirred for 30 minutes. Thereaction was then heated at 45° C. over 12 hours. The solvent wasremoved in vacuo and the residue was chromatographed on silica andeluted with EtOAc/Hexane 1:1 to 2:1 to yield 0.002 g of the titlecompound. MS(ES+)m/z=480.

Example 696N-[3-(10-Chloro-4-methoxy-5-oxo-5H-benzo[h][1,6]naphthyridin-6-yl)-cyclohexylmethyl]-benzamide

[0996] To 0.045 g (0.1 mmols) ofN-{[(1R,3S)-3-(3-acetyl-4-amino-5-chloro-2-oxohydroquinolyl)cyclohexyl]methyl}benzamideand 0.03 ml (0.3 mmols) of POCl₃ were dissolved in DMF (2 ml) at 0-5° C.The reaction was allowed to warm to rt. and stirred for 30 minutes. Thereaction was then heated at 45° C. over 12 hours. The reaction wascooled to rt. and NaOMe in MeOH (0.4 mmols) was added. The reaction washeated at 60° C. for 6 hours. The solvent was removed in vacuo. Theresidue was dissolved in CH₂Cl₂ and rinsed 1 time with 1N HCl, followedby 3 times with water. The solvent was removed in vacuo and the residuewas chromatographed on silica and eluted with EtOAc/Hexane 1:1 to 2:1 toyield 0.011 g of the title compound. MS(ES+)m/z=476.

Example 697N-[3-(10-Chloro-4-methylamino-5-oxo-5H-benzo[h][1,6]naphthyridin-6-yl)-cyclohexylmethyl]-benzamide

[0997] To 0.005 g (0.01 mmols) of a compound from Example 696 wascombined with 1.0 ml of aqueous methylamine 40% (excess) in ethanol (5ml). The reaction was refluxed for 30 minutes. MS(ES+)m/z=475.

Example 698 R(−)Amino-acetic acid[3-(9-chloro-3-methyloxo-4H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methylester hydrochloride

[0998] To a compound from Example 472 (96.7 mg, 0.16 mmol) was addedacetic acid saturated with HCl_((g)) (10 mL, ˜3N in HCl) and thesolution stirred vigorously at rt. for 1 hour. The reaction wasconcentrated, followed by addition of acetonitrile and concentration toassist in the removal of acetic acid (×2). The resulting white solid wastreated with ethyl ether, sonicated, and filtered to yield 68.4 mg ofthe title compound as a white solid, 79% yield. ¹H NMR: consistent withstructure. MS (ion spray) 523 (M⁺).

Example 699 S(+)Amino-acetic acid[3-(9-chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-phenyl-methylester hydrochloride

[0999] To a compound from Example 467 (70.0 mg, 0.11 mmol) was addedacetic acid saturated with HCl (10 mL, ˜3N in HCl) and the solutionstirred vigorously at rt. for 1 hour. The reaction was concentrated,followed by addition of acetonitrile and concentration to assist in theremoval of acetic acid (×2). The resulting white solid was treated withethyl ether, sonicated, and filtered to yield 37.84 mg of the titlecompound as a white solid, 60% yield. ¹H NMR: consistent with structure.MS (ion spray) 523 (M⁺).

Example 700{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentylcarbamoyl]-phenyl-methyl}-carbamicacid tert-butyl ester

[1000] A compound from Example 621 was converted to obtain the titlecompound with L-N-boc phenyl glycine as described for Example 515. ESMS:565 (M+1)+.

Example 701{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentylcarbamoyl]-phenyl-methyl}-trifluoroacetamide

[1001] A compound from Example 621 was converted to obtain the titlecompound with L-N-trifluoroacetyl phenyl glycine as described forExample 515. ESMS: 561 (M+1)+.

Example 703cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-(3-phenylureido)cyclohexane

[1002] To the suspension ofcis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-amino-cyclohexane(0.0446 g, 0.121 mmol) in 1 mL anhydrous THF at RT was added 2N NaOH(0.60 mL, 0.121 mmol). After 5 min. the phenylisocyanate (0.013 mL,0.121 mmol). After 20 min. the reaction was diluted with EtOAc, washedwith water and concentrated to near dryness. After sonication andfiltration a white solid (0.0412, 75%) was obtained. ESIMS m/e 451 ³⁵Cl(M⁺+1) and 453 ³⁷Cl (M⁺+1).

Example 7042-[(3S,1R)-3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-5H-isoquinoline-1,3-dione

[1003] To5-[(1S,3R)-3-(aminomethyl)cyclohexyl]-9-chloro-3-methyl-5-hydroisoxazolo[4,3-c]quinolin-4-one(60 mg, 0.17 mmol) and homophthalic acid (38 mg, 0.21 mmol) was addedxylenes (10 mL), and the reaction heated to reflux under nitrogenovernight with a Dean-Stark trap attached to effect removal of water.The solution was concentrated and dissolved in 20%isopropanol/chloroform, washed with 1.0N HCl (×2), saturated aqueoussodium bicarbonate solution, brine, dried over sodium sulfate andconcentrated. Purification by flash chromatography on silica gel(eluting with 20-25% ethyl acetate/hexane) gave 26 mg of the titlecompound as a clear oil, 31% yield. ¹H NMR: consistent with structure.MS (ion spray) 490 (M⁺), 488 (M⁻−1).

Example 705 3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazolecarboxylicacid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentyl]-amide

[1004] A compound from Example 620 was acylated with 2-chloro-5-fluorophenyl isoxazoyl chloride to obtain the title compound as described forExample 515. ESMS: 570 (M+1)⁺.

Example 7061-tert-Butyl-3-(2-chloro-6-fluoro-phenyl)-1H-pyrazole-4-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)cyclopentyl]-amide

[1005] A compound from Example 620 was converted to obtain the titlecompound with 4-(2-chloro,5-fluorophenyl)-1-t-butyl-pyrazole-3-carboxylic acid as described for Example515. ESMS: 610 (M+1)⁺.

Example 707{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentylcarbamoyl]-phenyl-methyl}-carbamicacid tert-butyl ester

[1006] A compound from Example 621 was converted to obtain the titlecompound with L-N-boc phenyl glycine as described for Example 515. ESMS:565 (M+1)+.

Example 7081R,3S-N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-cyclopentyl]-2-(3,4,5-trimethoxy-phenyl)-acetamide

[1007] A mixture of1R,3S-5-(3-amino-cyclopentylmethyl)₉-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one(15 mg, 0.045 mmol), 3,4,5-trimethoxyphenyl acetic acid (14 mg, 0.06mmol), EDC (12 mg, 0.06 mmol) and DMAP (2 mg) dissolved in DCM (10 mL)was stirred overnight at rt. The reaction mixture was diluted withadditional DCM (10 mL), washed with aq. NaHCO₃ (sat'd, 2×20 mL), water(2×20 mL), brine (2×20 mL), dried over sodium sulfate, filtered,evaporated, and chromatographed (Bond Elut, Si, 60 cc, 50% EtOAc inhexanes) to yield the desired product (10 mg, 41%). ESMS: 540 (M+1)⁺.

Example 709N-[3-(9Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl-cyclopentyl]-2-(3,4,5-trimethoxy-phenyl)-acetamide

[1008] To a stirred solution of racemic5-(3-aminocyclopentyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one(81 mg, 0.26 mmol) in CH₂Cl₂ (3 mL) was added 3,4,5-trimethoxy phenylacetic acid (114 mg, 0.52 mmol), Et₃N (0.1 mL, 0.50 mmol), HOBt (41 mg,0.3 mmol),DMAP (catalytic amount) and EDCI (72 mg, 0.38 mmol). Thereaction mixture was stirred at r.t. for 18 hours. The mixture wasdiluted with CH₂Cl₂, washed (brine), dried (Na₂SO₄), filtered andconcentrated. Column chromatography (silica gel, hexanes/ethyl acetate,gradient) gave the racemic title compound (89 mg, 66%). Mass Spectrum(FIA) (m/z) 454.0 (M+1)

Example 7102-[3S-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5yl)-R-cycloheptyl]-N-(3,4,5-trimethoxyphenyl)-acetamide

[1009] To a solution of 0.038 g (0.1 mmol) of2-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cycloheptyl]aceticacid in THF/DMF 1-1 (5 mL) was added 0.061 g (0.44 mmol) of1-hydroxy-7-azabenzotriazole and 0.86 g (0.44 mmol) of EDCI. After 40minutes, 0.083 g (0.44 mmol) of 3,4,5-trimethoxyaniline was added. After3.25 hours, the solvent was removed in vacuo and replaced with EtOAc.The organic layer was rinsed with 1N HCl, aq. NaHCO₃, then ×3 withwater. The organic layer was dried and the solvent was removed in vacuoto yield 0.026 g of the title compound. MS(ES+)m/z=554.

Example 7112-Acetylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-2-phenylacetamide

[1010] A compound as described in Example 633 (75 mg, 0.16 mmol) wascombined with 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol),1-hydroxybenzotriazole hydrate (33 mg, 0.24 mmol), and glacial aceticacid (0.015 mL, 0.24 mmol) in tetrahydrofuran (6 mL) and the mixturestirred over the weekend at ambient temperature. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with methanol/dichloromethane, which allowed for isolation of82 mg (99%) of product as an off white solid. MS(ES): (M+1)+507.1, 509.1m/z.

Example 7122-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-pyrrolidine-1-carboxylicacid benzyl ester

[1011] A compound as described in Example 660 (60 mg, 0.18 mmol) wascombined with DCC (56 mg, 0.27 mmol), HOBT (37 mg, 0.27 mmol), andN-carbobenzyloxy-L-proline (68 mg, 0.27 mmol) in tetrahydrofuran (6 mL)and the mixture stirred overnight at rt. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with MeOH/CH₂Cl₂, which allowed for isolation of 71 mg (70%)of product as a white solid. MS(ES): (M+1)+563.0, 565.0 m/z.

Example 7132-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-pyrrolidine-1-carboxylicacid benzyl ester

[1012] A compound as described in Example 660 (40 mg, 0.12 mmol) wascombined with DCC (37 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol), andN-carbobenzyloxy-D-proline (45 mg, 0.18 mmol) in tetrahydrofuran (4 mL)and the mixture stirred overnight at rt. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with MeOH/CH₂Cl₂, which allowed for isolation of 27 mg (40%)of product as a white solid. MS(ES): (M+1)+563.0, 565.0 m/z.

Example 714 1-Benzoyl-pyrrolidine-2-carboxylic acid[3-(9-chloro-3-methyloxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

[1013] A compound as described in Example 660 (40 mg, 0.12 mmol) wascombined with EDC, HOBT (25 mg, 0.18 mmol), and the compound frompreparation 104 (40 mg, 0.18 mmol) in tetrahydrofuran (6 mL) and themixture stirred overnight at rt The mixture was then concentrated invacuo and the residue loaded onto a silica gel column and eluted withEtOAc, which allowed for isolation of 58 mg (90%) of product as a whitesolid. MSS): (M+1)+533.3, 5535.3 m/z.

Example 715 1-Phenylacetyl-pyrrolidine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-amide

[1014] A compound as described in Example 660 (40 mg, 0.12 mmol) wascombined with EDC (37 mg, 0.18 mmol), HOBT (25 mg, 0.18 mmol), and thecompound from preparation 8R (42 mg, 0.18 mmol) in tetrahydrofuran (5mL) and the mixture stirred over the weekend at rt. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with EtOAc, which allowed for isolation of 54 mg (82%) ofproduct as a white solid. MS(ES): (M+1)+547.1 m/z.

Example 716 1-Benzyl-pyrrolidine-2-carboxylic acid[3-(9-chloro-3-methyl-4-oxo-5H-isdxazolo[4,3-c]quinolin-5-yl)cyclohexyl]-amide

[1015] A compound as described in Example 660 (40 mg, 0.12 mmol) wascombined with DCC (37 mg, 0.18 mmol), HOBT (25 mg, 0.18 mmol), and thecompound from preparation 107 (49 mg, 0.24 mmol) in tetrahydrofuran (5mL) and the mixture stirred over the weekend at rt. The mixture was thenconcentrated in vacuo and the residue loaded onto a silica gel columnand eluted with MeOH/CH₂Cl₂. A repeat of the chromatography yielded thetitle compound (56 mg, 89%). MS(ES): (M+1)+519.3, 520.3 m/z.

Example 717N-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylcarbamoyl]-methyl}-2-phenyl-acetamide

[1016]5-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydroiodide (70 mg, 0.19 mmol) was combined with EDC (47 mg, 0.25 mmol),1-hydroxy-7-azabenzo-triazole (34 mg, 0.25 mmol), N,N-diisopropylethylamine (0.10 mL, 0.58 mmol), DMAP (5 mg, cat.), and N-benzylglycinehydrochloride (50 mg, 0.25 mmol) in DMF(6 mL) and the mixture stirredovernight at rt. The mixture was then concentrated in vacuo and theresidue taken up in chloroform/MeOH and the organic solution washed withaqueous NaHCO₃. The organic solution was dried over Na₂SO₄ andconcentrated in vacuo. The residue was loaded onto a silica gel columnand eluted with MeOH/CH₂Cl₂, which allowed for the recovery of 32 mg(35%) of the free base. This material was dissolved in minimal EtOAc andtreated with excess diethyl ether/hydrochloric acid. Concentration ofthis mixture to dryness allowed for quantitative recovery of thehydrochloride salt as an off white solid. MS(ES): (M+1)+479.1, 481.2.

Example 718 1-methyl-piperidine-4-carboxylic acid{[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-phenyl-methyl}-amide

[1017] A product from Example 638 (50 mg; 0.108 mmol) was dissolved inanhydrous dimethylformamide (10 mL) under a nitrogen atmosphere, mixedwith 1-methyl-piperidine-4-carboxylic acid hydrochloride (58.0 mg; 0.323mmol; 3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (61.8 mg; 0.323 mmol; 3 equiv), 2,4,6-trimethylpyridine(86 μL; 0.645 mmol; 6 equiv), and 1-hydroxy-7-azabenzotriazole (43.9 mg;0.323 mmol; 3 equiv), and stirred overnight at room temperature. Thereaction solution was diluted with 2 volumes ethyl acetate, 10 volumeswater, and 1 volume saturated NaHCO_(3(aq)). The organic layer wasseparated and then washed with saturated NaCl_((aq)), dried overNa₂SO_(4(s)), filtered, and concentrated in vacuo. The resultingmaterial was purified by radial chromatography on a 2 mm thick silicagel rotor with a 2% then 4% methanol/dichloromethane (v/v) mobile phaseand finally a 2% methanol/0.5% triethylamine/dichloromethane (v/v/v)mobile phase. The desired product was isolated as a white solid in 74%yield (47 mg).

Example 719N-[3-(9-Acetylamino-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-benzamide

[1018] To a solution of a compound from Example 667 (0.025 g, 0.06 mmol)and AcOH (0.02 mL, 0.36 mmol) in DMF (1 mL) under N₂ was added EDCI(0.023 g, 0.12 mmol) and DMAP (0.002 g, 0.01 mmol). The solution wasstirred overnight, diluted with EtOAc, washed (H₂O then brine), dried(MgSO₄), filtered, and concentrated. Flash chromatography (silica gel,acetone/CH₂Cl₂ gradient) gave the title compound (0.023 g, 82%). MassSpectrum (ES+) (m/z) 473.3 [M+1]

Example 720N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-phenylamino-acetamide

[1019] Anhydrous dimethylformamide (10 mL) in a nitrogen atmosphere wasused to dissolve5-(3-aminocyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4one (50 mg; 0.151 mmol), N-phenylglycine (29.6 mg; 0.196 mmol; 1.3equiv), 1-hydroxy-7-azabenzotriazole (26.7 mg; 0.196 mmol; 1.3 equiv),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (37.6 mg;0.196 mmol; 1.3 equiv), and 2,4,6-trimethylpyridine (199 μL; 1.51 mmol;10 equiv). After overnight stirring at room temperature, the reactionsolution was treated in a manner similar to Example 159. The resultingmaterial was purified by three consecutive radial chromatography runs ona 2 mm thick silica gel rotor with a 1% methanol/dichloromethane (v/v)mobile phase, a 1% methanol/0.25% triethylamine/dichloromethane (v/v/v)mobile phase, and a 5% acetonitrile/dichloromethane mobile phase. Thedesired product was isolated as a white solid 56% yield (30 mg). MS(ES)calc'd: [M+H]⁺=465.16 m/z; [M−H]⁻=463.16 m/z; [M+OAc]⁻=523.16 m/z.Found: 465.1 m/z; 463.2 m/z; 523.2 m/z.

Example 7212-[3R-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-R-cycloheptyl]-N-(3,4,5-trimethoxyphenyl)-acetamide

[1020] In a manner similar to the preparation of Example 710, 0.055 g(0.14 mmol) of a compound from Example 680 was converted to a residuewhich was chromatographed on silica with EtOAc/hexanes 1/1 to yield0.044 g of the title compound. MS(ES+)m/z=553.9.

Example 7226-Chloro-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamide

[1021] A solution ofcis-5-[3-(aminomethyl)cyclohexyl]-9-chloro-3-methyl-5-hydroisoxazolo[4,5-c]quinolin-4-one(0.188 g, 0.54 mmol) and 6-chloro-nicotinic acid (0.103 g, 0.65 mmol) inDMF (10 mL) was treated with EDCI (0.125 g, 0.65 mmol) and HOAt (0.089g, 0.65 mmol). The reaction was then treated with excess Et₃N (0.167 g,1.62 mmol) and DMAP (6 mg, 0.05 mmol) and stirred at room temperatureovernight. The reaction was concentrated to a solid and then taken up in20% isopropanol in CHCl₃ (100 mL). This solution was transferred to aseparatory funnel and washed with a saturated sodium bicarbonatesolution (3×50 mL) and brine (2×50 mL). The organic solution was driedover sodium sulfate, filtered, and the solvent removed to afford a crudeyellow solid. The solid was purified using silica gel columnchromatography. The product was eluted using 50% EtOAc in CHCl₃. Thesolvent was removed in vacuo to afford 0.150 g (57%) of product as anoff white solid. MS m/z (ES+) 484.8 (M+H)⁺, (ES−) 482.8 (M−H)⁻, 542.8(M+CH3COO⁻)⁻.

Example 7232-tert-butylamino-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-pyridin-3-yl-acetamide

[1022] A compound from preparation 341 was saponified over 2 h with LiOH(1.5 equiv in water subsequently mixed with 1,4-dioxane). The carboxylicacid was isolated by rotary evaporation of the solution to dryness,acidification to pH 2 with 1 N HCl (aq), rotary evaporation of thesolution to dryness, and overnight drying at 0.1 torr. This material(1.3 equiv) was mixed with the free base of material from Preparation210 (100 mg; 0.301 mmol) in anhydrous DMF. Diisopropylethylamine (262μL; 0.392 mmol; 5 equiv),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (75.1 mg;0.392 mmol; 1.3 equiv), and 1-hydroxy-7-azabenzotriazole (53.3 mg; 0.392mmol; 1.3 equiv) were then added and the solution was stirred overnight,at rt. EtOAc (70 mL) and saturated NaHCO₃ (aq)(10 volumes) were addedand the organic layer was separated, washed with saturated NaCl(aq)(once), dried with Na₂SO₄ filtered, and concentrated in vacuo. Afterpurification by radial chromatography, 34 mg off-white solid wasisolated (22% yield). MS(ES) calc'd: [M+H]⁺=522.2 m/z; [M−H]⁻=520.2 m/z.Found: 522.2 m/z; 520.3 m/z.

Example 724N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-(2,2-dimethyl-propylamino)-2-pyridin-3-yl-acetamide

[1023] A compound from preparation 341 was used in a manner similar toExample 723 (substituting triethylamine for diisopropylethylamine) toprepare the title compound (24 mg white solid; 15% yield). MS(ES)calc'd: [M+H]⁺=536.2 m/z. Found: 536.2 m/z.

Example 725N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl)-2-(4-methyl-piperazin-1-yl)-2-pyridin-3-yl-acetamide

[1024] A compound from preparation 343 was used in a manner similar toExample 723 (substituting Et₃N for diisopropylethylamine) to prepare thedesired product. A 1% then 2% then 3% methanol/chloroform/trace Et₃N(v/v/v) mobile phase on a 2 mm chromatotron rotor was used to purify thedesired product (129 mg white solid; 78% yield). MS(exact mass) calc'd:[M+H]⁺=594.2381 m/z. Found: 594.2385 m/z.

Example 7262-(Benzenesulfonyl-pyridin-2-yl-amino)-N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexy]]-acetamide

[1025] To a solution of5-(3-amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydroiodide, 130 mg (0.28 mmol) in 10 mL of DMF was added 82 mg (0.28mmol) of (benzenesulfonyl-pyridin-2-yl-amino)-acetic acid (Bionet), 46mg (0.34 mmol) of 1-hydroxy-7-azabenzo-triazole, 66 mg (0.34 mmol) ofEDC, 5 mg of DMAP and 120 μL (0.84 mmol) of TEA. The reaction mixturewas stirred six days at rt. and was concentrated to dryness. The residuewas dissolved in 20% isopropanol/chloroform, washed with saturatedNaHCO₃, washed with brine, dried over Na₂SO₄, filtered and concentratedto dryness. The residue was purified by radial chromatography using aMeOH/chloroform gradient and concentrated to dryness. The residue wasslurried in ether/hexanes and concentrated to dryness to yield 79 mg(47%) of the title compound as a tan foam. MS (ion spray) 606.1 (M+).

Example 727N-[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexyl]-2-hydroxy-2-phenyl-acetamide

[1026] A solution of a compound from preparation 380 (0.08 g, 0.24mmol), R-Mandelic acid (0.04 g, 0.29 mmol), EDCI (0.06 g, 0.29 mmol),HOAt (0.04 g, 0.29 mmol) in DMF (10 mL) was treated with Et₃N (0.07 g,0.7 mmol) and DMAP (3.0 mg, 0.02 mmol) and stirred overnight at roomtemperature. The solution was then diluted in EtOAc (50 mL) and washedwith 5% citric acid (3×10 mL), sat'd sodium bicarbonate (3×10 mL), andbrine (2×10 mL). The solution was dried over sodium sulfate and purifiedby silica gel column chromatography. The solvent was removed in vacuo toafford 0.08 g (74%) as a white solid.

Example 728N-{[3-(9-Chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-methyl}-nicotinamide

[1027]5-(3-Amino-cyclohexyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-onehydroiodide (70 mg, 0.19 mmol) was combined with EDC (47 mg, 0.25 mmol),1-hydroxy-7-azabenzo-triazole (34 mg, 0.25 mmol), N,N-diisopropylethylamine (0.10 mL, 0.58 mmol), (5 mg, cat.), and nicotinuric acid (44 mg,0.24 mmol) in DMF(6 mL) and the mixture stirred overnight at rt. Themixture was then concentrated in vacuo and the residue taken up in waterand extracted with EtOAc. The combined extracts were dried over Na₂SO₄and concentrated in vacuo. The residue was loaded onto a silica gelcolumn and eluted with MeOH/CH₂Cl₂ which allowed for the recovery of 87mg (92%) of the title compound as a white solid. MS(ES): (M+1)+494.1,496.1.

Example 729N-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]-2-dimethylamino-2-pyridin-3-yl-acetamide

[1028] A compound from preparation 342 was used in a manner similar toExample 723 (substituting Et₃N for diisopropylethylamine) to prepare thedesired product. A 1% methanol/chloroform/trace triethylamine (v/v/v)mobile phase on a 2 mm chromatotron rotor was used to purify the desiredproduct (112 mg white solid; 76% yield). MS(exact mass) calc'd:[M+H]⁺=494.1959 m/z. Found: 494.1978 m/z.

Preparation 406 Pyridin-3-yl-(pyridin-2-yloxy)-acetic acid ethyl ester

[1029] A typical synthesis of bromopyridin-3-ylacetic acid ethyl esteris described: A solution of fresh lithium diisopropylamide (LDA) wasprepared at −10° C. from diisopropylamine (8.54 mL; 60.5 mmol) andn-butyllithium (37.8 mL of a 1.6 M hexanes solution; 12.1 mmol) andstirred for 10 min. After chilling the fresh LDA to −78° C., ethyl3-pyridylacetate (9.21 mL; 60.5 mmol) was added and the solution wasstirred another 10 min. Chlorotrimethylsilane (7.68 mL; 60.5 mmol) wasadded to the resulting opaque yellow slurry and the solution was stirred5 min. Finally a solution of 4-(dimethylamino)pyridinium tribromide(22.0 g; 60.5 mmol) in tetrahydrofuran was added and the reactionsolution was stirred 10 min. After warming to room temperature thereaction solution was quenched with saturated NH₄Cl_((aq)) and extractedtwice with ethyl acetate. The combined organic layer was washed oncewith saturated NaCl_((aq)), dried with Na₂SO_(4(s)), filtered, andconcentrated in vacuo. The resulting bromopyridin-3-ylacetic acid ethylester was an unstable brown oil and was therefore used immediately.

[1030] Silver carbonate (2.79 g; 10.1 mmol; 0.5 equiv) was refluxed intoluene (40 mL) for 0.5 h with 2-hydroxypyridine (1.92 g; 20.2 mmol; 1.0equiv) and an aliquot of bromo-pyridin-3-yl-acetic acid ethyl ester(approx. 4.9 g; 20.2 mmol), prepared as described above. After coolingto room temperature and filtration of the reaction mixture, thesupernatant was washed with saturated NaHCO_(3(aq)) (1×), water (1×),and saturated NaCl_((aq)) (1×). The organic layer was dried overNa₂SO_(4(s)), filtered, and concentrated in vacuo. Silica chromatographywith a 35% ethyl acetate/hexanes mobile phase produced a yellow oil(1.14 g; 22% yield) that solidified upon standing. MS(ES) calc'd:[M+H]+=259.2 m/z; [M−H]⁻=257.2 m/z. Found: 259.1 m/z; 257.2 m/z.REFERENCE: U. Schöllkopf, I. Hoppe, Justus Liebigs Ann. Chem. (1972)765, 153-170.

Example 730 Preparation a 1,3-cyclohexanedicarboxylic acid

[1031] To a suspension of isophthalic acid (500 g, 3 mol) in methanol(2.8 l) was added 5% Rhodium-on-alumina catalyst (50 g) and acetic acid(150 ml). The reaction mixture was shaken under hydrogen (50 psi) atroom temperature overnight. The mixture was filtered through celite. Tothis solution was added fresh 5% Rhodium-on-alumina catalyst (25 g), andthe mixture was shaken under 50 psi of hydrogen for another 24 hours.The final reaction mixture was filtered through celite. The solution wasconcentrated under vacuum to give 493 g of the title compound as a whitepowder (96.3% yield). m.p. 163-165° C.

Preparation b 3-Oxabicyclo[3.3.1)nonane-2,4-dione

[1032] A solution of dicyclohexylcarbodiimide (200 g, 1.16 mol) inCH₂Cl₂ (1000 ml) was added dropwise to a suspension of compound frompreparation a (257 g, 1.25 mol) in CH₂Cl₂ (550 ml), and the mixture wasstirred at room temperature for 4 hours. The precipitateddicyclohexylurea was filtered and washed several times with cold CH₂Cl₂(200 ml×3). The combined organic layer was concentrated to give a whitesolid, which was suspended in MTBE (900 ml). This solid was collected byfiltration, washed with MTBE (250 ml), and dried under house vacuum togive the title compound (137 g). The filtrate was concentrated to aresidue, which was suspended in MTBE (250 ml) to give another 31 ganhydride. The total yield was 168 g (94%). m.p. 138-140° C.

Preparation c cis-1,3-Cyclohexanedicarboxylic acid diethyl ester

[1033] To a solution of compound from preparation b (31 g, 0.2 mol) inethanol (anhydrous, 310 ml) was added p-toluenesulfonic acid monohydrate(1.9 g, 10 mmol, 0.05 equiv.) and triethyl orthoformate (50 ml, 0.3mol). The reaction mixture was stirred at 60° C. overnight. Thevolatiles were stripped and the residue was diluted with ethyl acetate(250 ml), washed with water (120 ml) and brine (100 ml), and dried overMgSO₄. After filtration and evaporation, the residue was purified bychromatography. Eluting the column with 10% ethyl acetate in hexaneafforded the title compound (40 g, 87.7% yield).

[1034]¹H NMR: (500 MHz, CDCl₃) δ 4.11 (q, J=7.0 Hz, 4H), 2.29 (dt, 2H),2.11 (dd, 1H), 1.97 (m, 2H), 1.98 (m, 1H), 1.53 (q, J=12.5 Hz, 2H),1.30-1.40 (m, 2H), 1.25 (t, J=7.0 Hz, 6H).

Preparation d 1,3-Cyclohexanedicarboxylic acid, monoethyl ester (1R,3S)

[1035] To a suspension of compound from preparation c (40 g, 17.5 mmol)in pH 7.2 phosphate buffer [0.2 M) (1.21) was added lipase AY30 (Amano,16.7 g). The mixture was stirred vigorously at room temperature for 30hours. The mixture was acidified with 10-15% HCl to pH<2, and extractedwith ethyl acetate (500 ml×2). The combined organic solution was washedwith aqueous 10% Na₂CO₃ (100 ml×2) and water (100 ml×2). The combinedaqueous layers were washed again with ethyl acetate (150 ml) and thenacidified with 10-15% HCl to pH<2. The acidified aqueous was thenextracted with ethyl acetate (150 ml×3). The combined organic solutionwas dried over MgSO₄. After filtration and concentration the titlecompound (35.6 g, 100% yield) was obtained.

[1036]¹H NMR (500 MHz, CDCl₃) δ 4.12 (q, J=7.0 Hz, 2H), 2.20-2.40 (m,3H), 1.85-2.05 (m, 3H), 1.5 (q, 2H), 1.35 (m, 2H), 1.24 (t, J=7.0 Hz,3H).

Preparation e Ethyl-[3-N-(methylcarbamate)-cyclohexyl]-carboxylate(1R,3S)

[1037] A solution of a compound from preparation d (73 g, 365 mmol) intoluene (750 ml) was heated to reflux using a Dean-Stark trap toseparate trace amounts of water. After collecting about 10 ml of water,the mixture was cooled down to about 40-50° C. To this mixture was addedtriethylamine (56 ml, 0.4 mol), and diphenylphosphoryl azide (86.5 ml,0.4 mol). The reaction mixture was stirred at 110° C. for 60 min, cooledto 70° C., and methanol (64 g, 2 mol) was added with stirring. Afteraddition, the final reaction mixture was then heated to 85° C.overnight. After cooling to room temperature, the mixture was dilutedwith ethyl acetate (700 ml) and washed with water (500 ml). The aqueouslayer was extracted with ethyl acetate (500 ml×2). The combined organicsolution was washed again with water (500 ml) and brine (500 ml). Afterdrying over MgSO₄ and concentration under reduced pressure, the titlecompound was obtained as a colorless oil (86 g, 100%).

[1038]¹H NMR: (300 MHz, CDCl₃) δ 4.60 (sb, 1H), 4.13 (q, 2H), 3.65 (s,3H), 3.50 (sb, 1), 2.38 (t, 1H), 2.23 (d, 1H), 2.00-1.80 (m, 3H), 1.24(t, 3H), 1.12-0.95 (m, 1H).

Preparation f Ethyl-((1R, 3S)-3-{[3-(2-chloro-6-fluorophenyl5-methylisoxazolyl]carbonyl-amino}cyclohexyl)-carboxylate

[1039] To a solution of compound from preparation e (86 g, 365 mmol) inCH₂Cl₂ (750 ml) was added iodotrimethylsilane (100 g, 500 mmol) in oneportion, at room temperature. The reaction mixture was stirred for 2hours at ambient temperature, cooled to 0-5° C., and methanol (50 ml)was added. After stirring 15 minutes, the solution was concentratedunder reduced pressure. The residue was dissolved in THF (1 l). To thissolution was added water (0.5 l), potassium carbonate (138 g, 1 mol),and a solution of3-(6-fluoro-2-chlorophenyl)-5-methylisooxazole-4-carboxyryl chloride(110 g, 0.4 mol) in 250 ml]THF, dropwise. After the addition, thereaction mixture was heated to room temperature and stirred for 12hours. THF was removed under house vacuum, water (250 ml) was added, andthe mixture was extracted with ethyl acetate (500 ml×3). The combinedorganic solution was washed with saturated sodium thiosulfate (150 ml),water (500 ml), brine (500 ml) and then dried over MgSO₄. Afterfiltration and evaporation under vacuum, the residue was purified byrecrystallization from MTBE (250 ml). Repeating this recrystallizationprocedure three times provided the title compound (122.7 g, 82.5% yield)as a white powder. IR: v_(max), (film) 3429, 3011, 2940, 1725, 1662,1187 cm⁻¹.

Preparation g Ethyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quindin-5-yl)-cyclohexyl]-carboxylate

[1040] To a solution of compound from preparation f (78 g, 190 mmol) inDMF (750 ml) was added a solution of KHMDS ([0.5M], 400 ml, 200 mmol).The temperature was kept at 25° C. by using an ice-bath. After theaddition was complete, the reaction mixture was analyzed by TLC (silicagel, 50% EtOAc in hexane) and found to be complete. Water (1 l) wasadded and the mixture was extracted with EtOAc (800 ml×3). The combinedorganic solution was washed with 1N HCl (250 ml), water (250 ml), brine(250 ml), dried over MgSO₄ and concentrated to give a residue which waspurified by recrystallization from MTBE (500 ml) to afford 66 g of thetitle compound as a light yellow powder (89.0% yield).

[1041] IR: v_(max) (film) 3030, 1720, 1670, 1220 cm⁻¹.

Preparation h (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarboxylic acid

[1042] To a solution of compound from preparation g (62 g, 160 mmol) inTHF (600 ml) was added 5N aqueous sodium hydroxide (120 ml) at roomtemperature. The reaction mixture was heated to 60° C. for 15 hours withstirring. After cooling to room temperature, water (750 ml) was addedand the mixture was washed with ethyl acetate (500 ml). The aqueousphase was separated and acidified with 15% HCl to pH<2. The aqueousphase was then extracted with methylene chloride (1000 ml×3). Thecombined organic extracts were washed again with water (500 ml), brine(500 ml), and dried over MgSO₄. After filtration and evaporation undervacuum, the dark brown residue was suspended in MTBE (1000 ml), andrefrigerated overnight. The mixture was filtered to afford 55.45 g(96.4%) of bright yellow product. IR: v., (Film) 3200, 2936, 1726, 1643,1595, 1173 cm¹.

Preparation i 2-methyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]carbamate

[1043] To a suspension of compound from preparation 8 (55.4 g, 154 mmol)in toluene (1 l) was added triethylamine (23.7 ml, 170 mmol), anddiphenylphosphoryl azide (36.5 ml, 170 mmol). The reaction mixture wasstirred at 110° C. for 2 hours during which time a solution formed. Thesolution was cooled to 80° C. and methanol (25 g, 0.77 mol) was addedwith stirring. The solution was warmed to 85° C. for 22 hours. Aftercooling to room temperature, the toluene was removed under reducedpressure and the residue was dissolved in dichloromethane (31) andwashed with water (1 l). The aqueous phase was extracted withdichloromethane (11×2) and the combined organic solution was washedagain with water (500 ml) and brine (500 ml). After drying over MgSO₄,the solution was concentrated under vacuum. The crude product waspurified by crystallization (CH₂Cl₂/MTBE, 0.5 ½ l) to afford the tidecompound (46.6 g, 78.2%). [a]D+49.2°, [α]₃₆₅+263.3 0 (c, 0.56; CHCl₃).The filtrate was concentrated to a residue, which was purified bychromatography to obtain a second crop of product (5.1 g). The totalyield was 86.8%.

[1044] IR v_(max) (Film) 3410, 3020, 2950, 1710, 1670, 1220 cm⁻¹.

Preparation i (1R,3S)3-(9-Chloro-3-methyl-4-oxo-H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl alcohol

[1045] To a solution of compound from preparation h (4.4 g, 12.2 mmol)in THF (45 ml) was added borane-methyl sulfide complex (2.0 M solutionin THF, 12.5 ml, 25 mmol) dropwise at 0° C. When the addition wascomplete, the reaction mixture was allowed to warm-to-room temperatureand was stirred for one hour. Methanol (10 ml) was added slowly (gasgenerated) with stirring. The reaction mixture was then poured intoice-water (60 ml) and extracted with ethyl acetate (100 ml×3). Thecombined organic solution was washed with 1N HCl (50 ml), brine (50 ml),and dried over MgSO₄. After filtration and evaporation under vacuum, theyellow title compound (4.34 g, 100%) was obtained. M.S.: m/z 347 (M⁺+1).

Preparation k (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl alcohol mesylate

[1046] To a stirred solution of compound from preparation j (4.32 g.12.5 mol) in pyridine (25 ml) was added DMAP (10 mg) and methanesulfonylchloride (1.16 ml, 15 mmol, 1.2 equiv) and the resulting mixture wasstirred at room temperature for 1.5 h. Water (100 ml) was added, and themixture was extracted with ethyl acetate (150 ml×2). The combinedorganic extracts were washed again with brine (100 ml), dried (MgSO₄)and concentrated. The residue was suspended in MTBE (25 ml) and filteredto obtain the title compound as a solid (4.65 g, 87.8%). [α]_(D)+8.71°,[α]₃₆₅+58.7° (c, 0.358; CHCl₃).

Preparation m (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl azide

[1047] A mixture of a compound from preparation k (4.6 g, 10.8 mmol),sodium azide (2.15 g, 33 mmol) and DMF (45 ml) was heated to 60° C. andstirred for 24 h. After cooling to room temperature, the mixture waspoured into 150 ml of ice-water and extracted with MTBE (200 ml×2). Thecombined organic extracts were washed with brine (150 ml) and dried overMgSO₄. After filtration and concentration, the residue waschromatographed on silica gel using 30% ethyl acetate/hexane to give thetitle compound as a white powder (3.82 g, 95%). [a]D+17.20,[a)]36+105.7° (c, 0.864; CHCl₃).

Preparation n (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl amine

[1048] To a solution of a compound from preparation m (2.0 g, 5.4 mmol)in ethyl acetate (25 ml) was added 5% Pd/C catalyst (200 mg). Thereaction mixture was shaken under hydrogen (50 psi) at room temperaturefor 2 days. The mixture was filtered through celite and the filtrate wasconcentrated under vacuum to give the title compound as a solid (1.85 g,99.2%).

[1049]¹H NMR: (300 MHz, CDCl₃) δ 7.45 (t, 1.5H), 7.34 (d, 1.5H), 2.90(s, 3H), 2.62 (m, 2H), 2.59 (br s, 1H), 2.42 (br s, 1H), 2.00 (m, 1H),1.84 (m, 4H), 1.50 (m, 2H), 1.12 (m, 1H).

Preparation oEthyl-((1R,3S)-3-{[5-(2-chloro-6-fluorophenyl)-3-methylisoxazol-4-yl]carbonyl-amino}cyclohexyl)-carboxylate

[1050] To a solution of a compound from preparation d (42 g, 182 mmol)in CH₂Cl₂ (400 ml) was added iodotrimethylsilane (36.5 ml, 255 mmol) inone portion at room temperature. The reaction mixture was stirred for 2hours at ambient temperature and then cooled down to 0-5° C. To thismixture was added methanol (50 ml) and the mixture was stirred 15minutes and concentrated under reduced pressure. The residue wasdissolved in THF (300 ml), and water (150 ml) and potassium carbonate(62 g, 0.45 mol) were added. To the resulting mixture was slowly added asolution of 5-(2-chloro-6-fluorophenyl)-3-methyl-isooxazole-4-carboxylchloride (50 g, 182 mmol) in 50 ml of THF. After the addition, thereaction mixture was allowed to warm to room temperature and was stirredfor 12 hours. THF was removed under house vacuum, water (150 ml) wasadded and the mixture was extracted with ethyl acetate (500 ml×2). Thecombined organic solution was washed with water (250 ml), brine (250 ml)and dried over MgSO₄. After filtration and evaporation under vacuum, theresidue was purified by silica gel chromatography (30% ethyl acetate inhexane) to obtain the title compound (62.57 g, 84.3% yield) as a whitepowder. M.S.: m/z 409 (M+, 100%).

Preparation p Ethyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quindin-5-yl)-cyclohexyl]-carboxylate

[1051] To a 0-5° C. solution of a compound from preparation o (61.5 g,0.15 mol) in DMF (500 ml) was added a solution of KHMDS (340 ml, [0.5M],0.17 mol) in toluene. After the addition was complete, the mixture wasstirred at ambient temperature for 15 minutes and analyzed by TLC(silica gel, 50% EtOAc in hexane), which indicated completion of thereaction (TLC showed a minor by-product spot along with the majorproduct spot). Water (1 l) was added and the mixture was extracted withEtOAc (800 ml×3). The combined organic extracts were washed with water(250 ml), brine (250 ml), dried over MgSO₄ and concentrated to aresidue. The residue was purified by recrystallization from MTBE (200ml) to obtain 28.12 g of the title compound. The filtrate wasconcentrated and purified by silica gel chromatography to obtain anadditional 12.4 g of the title compound (40.52 g total, 69.3% yield).

[1052] M.S.: m/z 389 (M⁺+1, 100%).

Preparation q (1R,3S)3-(9-chloro-3-methyl-4oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylcarboxylic acid

[1053] To a solution of a compound from preparation p (40 g, 103 mmol)in THF (350 ml) was added 5N aqueous sodium hydroxide (88 ml) at roomtemperature. The reaction mixture was warmed to 60° C. and stirred for15 hours. After cooling to room temperature, water (500 ml) was addedand the mixture was washed with ethyl acetate (500 ml). The aqueousphase was separated and acidified with 15% HCl to pH<2. The precipitatewas collected by filtration and washed with ethyl acetate (250 ml). Thefiltrate was extracted with ethyl acetate (500 ml) and the combinedorganic solution was washed again with water (200 ml), brine (200 ml),and dried over MgSO₄. After filtration and evaporation under vacuum, theresidue was combined with the precipitate obtained from acidification ofthe reaction mixture and suspended in MTBE (500 ml). The suspension wasfiltered to afford the title compound as a bright yellow product (36.0g, 100%). M.S.: m/e 361 (M⁺+1, 100%);

Preparation r (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylmethyl alcohol

[1054] To a suspension of a compound from preparation q (37.52 g, 0.104mmol) in THF (350 ml) was added borane-methyl sulfide complex in 140 mlof THF (26 ml, 0.27 mol) dropwise at 0° C. After the addition, thereaction mixture was stirred at 0-5° C. for one hour. TLC (3:1EtOAc/hexane) indicated the completion of the reaction. Methanol (50 ml)was added slowly (gas generated) with stirring, followed by aqueous 10%HCl (50 ml). After stirring for 15 minutes, the reaction mixture waspoured into ice water (250 ml) and extracted with ethyl acetate (350ml×2). The combined organic solution was washed with brine (300 ml),dried over MgSO₄ and concentrated under vacuum. The crude product waspurified by silica gel chromatography (EtOAc/hexane, 1:1) to give thetitle compound (32.5 g, 90%). M.S.: m/e 347 (M⁺+1).

Preparation s (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)cyclohexylmethyl alcohol mesylate

[1055] To a stirred solution of a compound from preparation r (32.25 g.93.2 mmol) in pyridine (270 ml) was added DMAP (20 mg) andmethanesulfonyl chloride (7.9 ml, 102 mmol, 1.1 equiv.). The mixture wasstirred at room temperature for 1.5 hours. Water (500 ml) and EtOAc/MTBE(500 ml, 1:1) were added causing the product to precipitate. The solidwas collected by filtration, washed with M E (150 ml) and dried undervacuum to provide 29.35 g as a white powder. The filtrate was washedagain with brine (300 ml), dried (MgSO₄), and concentrated. The residuewas suspended in MTBE (50 ml) and filtered to give a second crop of thetitle compound (9.5 g, total yield: 38.8 g, 99.3%). M.S.: m/e 425(M*+1).

Preparation t (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylmethyl azide

[1056] A mixture of a compound from preparation s (38.2 g, 90 mmol),sodium azide (21 g, 0.32 mol), and DMF (350 ml) was heated to 60° C.with stirring for 20 hours. After cooling to room temperature, themixture was poured into ice-water (500 ml) and extracted with EtOAc (500ml×2). The combined organic phases were washed with brine (250 ml) anddried over MgSO₄. After filtration and evaporation, the residue waschromatographed on silica gel using 30% ethyl acetate/hexane to give thetitle compound as a white powder (28.2 g, 84.4%).

[1057] M.S.: m/e 372 (M⁺+1).

Preparation u 1,3-cyclohexanedicarboxylic acid

[1058] To a suspension of isophthalic acid (5.0 g, 30.1 mmol) in 45 mlof acetic acid was added a slurry of 0.1 g of platinum oxide in 5 ml ofacetic acid. The resulting mixture was stirred under 50 psi of hydrogenat 25° C. for 16 hours. NMR analysis (DMSO-d₆) at this time showedcomplete reduction of starting material. The reaction mixture wasfiltered through Celite and the filter cake was rinsed with methanol.The combined filtrate and washes were concentrated under reducedpressure, using heptane to azeotropically remove residual acetic acid.Trituration of the resultant semi-solid with heptane and filtration ofthe precipitate provided 4.92 g (95%) of the title compound as a whitepowder. mp: 163-165° C.

Preparation v 3-Oxabicyclo[3.3.1]nonane-2,4-dione

[1059] A suspension of 1,3-cyclohexanedicarboxylic acid (490 g, 2.88mol) in acetic anhydride (1500 ml) was heated to 140° C., refluxing for2 hours. Acetic anhydride was then removed with distillation (oil bath180° C.). To the residue was added acetic anhydride (1000 ml) andrefluxed at 140° C. for 1 hour. The acetic anhydride was removed againwith distillation (under house vacuum, about 50° C.). After crystalsappeared, the mixture was cooled to room temperature and MTBE (400 ml)was added. The mixture was then cooled to 0-5° C. The crystals werefiltered, washed with MTBE (250 ml), and dried under house vacuum togive the title compound (382 g). The filtrate was concentrated to aresidue and suspended in MTBE (100 ml) to give the second crop of thetitle compound (14.0 g). The total yield was 396 g (90.5%). Mp 138-140°C.

Example A Benzoyl[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexyl]amide

[1060] To a solution of the compound from preparation i (160 mg, 0.41mmol) in CH₂Cl₂ (3 ml) was added iodotrimethylsilane (124 mg, 0.62 mmol)in one portion, at room temperature. The reaction mixture was stirredfor 2 hours at ambient temperature and cooled to 0-5° C. Methanol (1 ml)was added and the mixture was stirred for 15 minutes and concentratedunder reduced pressure. The residue was dissolved in THF (2 ml). To thissolution was added water (1 ml), potassium carbonate (210 mg, 1.5 mmol),and benzoyl chloride (60 ml, 0.5 mmol). The resultant mixture wasstirred at room temperature for 2 hours. THF was removed under housevacuum, water (15 ml) was added, and the mixture was extracted withethyl acetate (15 ml×2). The combined organic extracts were washed withsaturated sodium thiosulfate (10 ml), brine (10 ml) and dried overMgSO₄. After filtration and evaporation under vacuum, the residue waspurified by silica gel chromatography (35% EtOAc/hexane) to obtain thetitle compound (145 mg, 81.0% yield) as an off-white powder.

[1061]¹H NMR: (300 MD, DMSO-d₆) δ 8.40 (d, 1H), 7.82 (m, 4H), 7.62 (t,1H), 7.43 (m, 4H), 4.5 (br s, 1H), 4.05 (m, 1H), 2.82 (s, 3H), 2.78 (m,1H), 1.88 (m, 4H), 1.71 (m, 2H), 1.60 (m, 1H), 1.41 (m, 1H).

Example B 4-Fluoro-3-pyridyl-carboxyl-(1R,3S)3-(9-chloro-3-methyl-4-oxo-SH-isoxazolo[4,3-c]quinolin-5-yl)cyclohexylmethyl amide

[1062] To a solution of a compound from preparation n (466 mg, 1.35mmol) in THF/H₂O (5 ml/2.5 ml) was added potassium carbonate (690 mg, 5mmol) and 2-fluoro-pyridine-4-carboxyl chloride (240 mg, 1.5 mmol) atroom temperature. After the addition, the reaction mixture was stirredfor 2 hours at ambient temperature. Water (50 ml) was added and themixture was extracted with dichloromethane (50 ml×2). The combinedorganic extracts were washed with water (35 ml), brine (35 ml) and driedover MgSO₄. After filtration, the filtrate was concentrated to a residue(720 mg) which was purified by silica gel chromatography (ethylacetate/dichloromethane, 1:2) to give the title compound (450 mg, 71.0%)as a white powder.

[1063] M.S.: m/z 469 (M⁺+1, 100%).

Example C 4-fluoro-3-pyridyl-carboxyl-(1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,5-c]quinolin-5-yl)-cyclohexylmethyl amide

[1064] To a solution of the compound from preparation t (2.0 g, 5.4mmol) in THF (120 ml) was added triphenylphosphine (10.5 g, 40 mmol) andwater (25 ml). The mixture was stirred under nitrogen at roomtemperature overnight. To the reaction mixture was added 15% aqueous HCl(15 ml) and the mixture was stirred for 30 minutes. The mixture was thenpoured into water (200 ml) and washed with ethyl acetate/BE (150 ml/50ml). Some product precipitated and was suspended in the aqueous layer.The organic layer was separated and washed with water (70 ml). Thecombined aqueous phases (about 270 ml) were washed again with ethylacetate/MTBE (100 ml/50 ml). To the aqueous suspension was added Th (270ml), K₂CO₃ (41 g, 0.3 mol) and 2-fluoropyridine-4-carboxyl chloride (6.4g, 40 mmol) at room temperature. After the addition, the reactionmixture was stirred for 20 hours. The mixture was extracted with ethylacetate (250 ml×2) and the combined organic extracts were washed withbrine (200 ml), and dried over MgSO₄. After filtration, the filtrate wasconcentrated to give (16.5 g, 99.7%) of a white powder. The product wasfurther purified by recrystallization from methanol to afford the titlecompound (14.0 g, 85%).

[1065] M.S.: m/e 469 (M⁺+1).

Example DN-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamide

[1066] To a solution of (1R,3S)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl amide (700 mg, 2.0 mmol) in 35 mL of dichloromethane was added440 mg (2.4 mmol) of nicotinoyl chloride hydrochloride, 0.85 mL (6.0mmol) of triethylamine and 5 mg of 4-dimethylaminopyridine. The reactionmixture was stirred overnight at ambient temperature, then washed with 1N hydrochloric acid. The aqueous layer was extracted with 20%isopropanol/chloroform. The combined organics were washed with saturatedsodium carbonate, brine, dried over sodium sulfate, filtered andconcentrated to dryness. The residue was chromatographed on silica gelusing methanol/chloroform as eluent to yield 740 mg (82%) of the desiredisomer as a white solid. MS (ion spray) 451.1 (M+1).

Example E6-Chloro-N-[(1R,3S)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylmethyl]-nicotinamide

[1067] To a solution of5-[3-(aminomethyl)cyclohexyl]-9-chloro-3-methyl-5-hydroisoxazolo[4,3-c]quinolin-4-oneHCl (86 mg, 0.22 mmol) in 20 mL of N,N-dimethylformamide was added 62 μL(0.45 mmol) of triethylamine, 43 mg (0.27 mmol) of 6-chloronicotinicacid, 36 mg (0.27 mmol) of 1-hydroxy-7-azabenzo-triazole, 51 mg (0.27mmol) of 1-(3-dimethylamino-propyl)₃-ethyl-carbodiimide hydrochlorideand 5 mg of 4-dimethylaminopyridine. The reaction mixture was stirredovernight at ambient temperature and concentrated to dryness. Theresidue was partitioned between chloroform and saturated sodiumbicarbonate. The mixture was washed with saturated sodium bicarbonate,water, brine, dried over sodium sulfate, filtered and concentrated todryness. The residue was chromatographed on silica gel usingmethanol/chloroform as eluent and concentrated to dryness. The residuewas slurried in ether/hexanes and concentrated to dryness to yield 77 mg(71%) of the desired isomer as a white foam. MS (ion spray) 485.1 (M+).

[1068] The compounds of the invention are inhibitors of MRP1. Thus, thecompounds of the invention may be used to inhibit any neoplasm havingintrinsic and/or acquired resistance, conferred in part or in total byMRP1, to an oncolytic or oncolytics. In other words, treatment of such aneoplasm with an effective amount of a compound of this invention willcause the neoplasm to be more sensitive to chemotherapy that wasrendered less efficacious by MRP1.

[1069] Camptosar, melphalan, paclitaxel, vinorelbine, mitoxantrone,doxorubicin, daunorubicin, epirubicin, vincristine, and etopsoside areoncolytics that are substrates of MRP1. See Cole, et. al.,“Pharmacological Characterization of Multidrug Resistant MRP-transfectedHuman Tumor Cells”, Cancer Research, 54:5902-5910, 1994. Since MRP1 isubiquitous in mammals, particularly humans, Nooter, K, et. al.,“Expression of the Multidrug Resistance-Associated Protein (MRP) Gene inHuman Cancers”, Clin. Can. Res., 1:1301-1310, (1995), chemotherapy whosegoal is to inhibit a neoplasm employing any of those agents has thepotential to be rendered less efficacious by MRP1. Thus, neoplasms ofthe bladder, bone, breast, lung(small-cell), testis, and thyroid andmore specific types of cancer such as acute lymphoblastic andmyeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue sarcoma,Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma may beinhibited with a combination of one or more of the above oncolytics anda compound of this invention.

[1070] The biological activity of the compounds of the present inventionwas evaluated employing an initial screening assay which rapidly andaccurately measured the activity of the tested compound in inhibitingMRP1 or MDR1. Assays useful for evaluating this reversing capability arewell known in the art See, e.g., T. McGrath, et al., BiochemicalPharmacology, 38:3611, 1989; D. Marquardt and M.S. Center, CancerResearch, 52:3157, 1992; D. Marquardt, et al., Cancer Research, 50:1426,1990; and Cole, et. al., Cancer Research, 54: 5902-5910, 1994.

[1071] Assay for Reversal of MRP1-Mediated Doxorubicin Resistance andMDR1-Mediated Vincristine Resistance: HL60/Adr and HL60/Vinc arecontinuous cell lines, which were selected for doxorubicin andvincristine resistance respectively by culturing HL60, a human acutemyeloblastic leukemia cell line, in increasing concentrations ofdoxorubicin or vincristine until a highly resistant variant wasattained.

[1072] HL60/Adr and HL60/Vinc cells were grown in RPMI 1640 (Gibco)containing 10% fetal bovine serum (FBS) and 50 μg/ml GENTAMICIN™(Sigma). Cells were harvested; washed twice with assay medium (same asculture media); counted; and diluted to 1×10⁵ cells/ml in assay medium.One hundred microliters of cells were aliquoted into wells of a 96 welltissue culture plate. Two columns of each 96 well plate served as anegative control and received assay medium containing no cells.

[1073] Test compounds and reference compounds were dissolved in dimethylsulfoxide (DMSO) at a concentration of 5 mM. Samples were diluted inassay medium and 25 μl of each test compound was added to 8 wells. Assaystandards were run in quadruplicate. Assay media was added to half ofthe wells and doxorubicin to the other half of the wells to achieve afinal volume of 150 μl per well.

[1074] The plates were incubated at 37° C. for 72 hours in a humidifiedincubator with a 5% carbon dioxide atmosphere. Cell viability andvitality was measured by oxidation of a alamarBlue™ fluorescent dyeusing standard conditions. The plates were incubated for 3 hours at 37°C. Fluorescence was determined using 550 nm excitation and 590 nmemission using a microtitre plate reader.

[1075] The ability of a test compound to reverse the resistance ofHL60/Adr and HL60/Vinc cells to doxorubicin was determined by comparisonof the absorbance of the wells containing a test compound in addition tothe oncolytic (doxorubicin) with the absorbance of wells containing theoncolytic without a test compound. Controls were used to eliminatebackground and to ensure the results were not artifactual. The resultsof the assay are expressed as percent inhibition of cell growth. Theoncolytic alone at the tested concentration minimally inhibits thegrowth of HL60/Adr or HL60/Vinc cells.

[1076] Representative compounds of formula I demonstrated a significanteffect in reversing the MRP1 multiple drug resistance. Many of thecompounds showed very significant enhancement of activity in combinationwith the oncolytic agent as opposed to the oncolytic agent alone. Inaddition, a large majority of the compounds tested displayed asignificant degree of selective inhibition of the HL0/Adr cell line overthe HL60/Vinc cell line.

[1077] When administering an oncolytic in practicing the methods of thisinvention, the amount of oncolytic employed will be variable. It shouldbe understood that the amount of the oncolytic actually administeredwill be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual oncolytic administered, the age, weight,and response of the individual patient (mammal), and the severity of thepatient's symptoms. Of course, the amount of oncolytic administeredshould be decided and closely monitored by that patient's physician.After deciding on the oncolytic or oncolytics to employ, “ThePhysician's Desk Reference®”, published by Medical Economics Company atMontvale, N.J. 07645-1742, is a helpful resource to the physician indeciding on amounts of the oncolytic to administer and is updatedannually.

[1078] Preferred formulations, and the methods of this inventionemploying those formulations, are those which do not contain anoncolytic. Thus, it is preferred to administer the compounds of thisinvention separately from the oncolytic. The oncolytics mentioned inthis specification are commercially available and may be purchased inpre-formulated forms suitable for the methods of this invention.

[1079] The compounds of formula I alone, or optionally in combinationwith an oncolytic, are usually administered in the form ofpharmaceutical formulations. These formulations can be administered by avariety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Such formulations areprepared in a manner well known in the pharmaceutical art and compriseat least one active compound of formula I.

[1080] The present invention also includes methods employingpharmaceutical formulations which contain, as the active ingredient, thecompounds of formula I, and optionally an oncolytic, associated withpharmaceutical carriers. In making the formulations of the presentinvention the active ingredient(s) is usually mixed with an excipient,diluted by an excipient, or enclosed within such a carrier which can bein the form of a capsule, sachet, paper or other container. When theexcipient serves as a diluent, it can be a solid, semi-solid, or liquidmaterial, which acts as a vehicle, carrier or medium for the activeingredient. Thus, the formulations can be in the form of tablets, pills,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium),ointments containing for example up to 10% by weight of the activecompound, soft and hard gelatin capsules, suppositories, sterileinjectable solutions, and sterile packaged powders.

[1081] In preparing a formulation, it may be necessary to mill theactive compound(s) to provide the appropriate particle size prior tocombining with the other ingredients. If the active compound(s) issubstantially insoluble, it ordinarily is milled to a particle size ofless than 200 mesh. If the active compound(s) is substantially watersoluble, the particle size is normally adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g., about 40mesh.

[1082] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Theformulations of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

[1083] The formulations are preferably formulated in a unit dosage form,each dosage containing from about 5 to about 100 mg, more usually about10 to about 30 mg, of each active ingredient. The term “unit dosageform” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

[1084] The compounds of formula I are effective over a wide dosagerange. For example, dosages per day normally fall within the range ofabout 0.5 to about 30 mg/kg of body weight. In the treatment of adulthumans, the range of about 1 to about 15 mg/kg/day, in single or divideddose, is especially preferred. However, it will be understood that theamount of the compound actually administered will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered, the age, weight, and response of the individualpatient, and the severity of the patient's symptoms, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day.

[1085] For preparing solid formulations such as tablets the principalactive ingredient(s) is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient(s) is dispersed evenly throughout the formulation so that theformulation may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from 1 to about 500 mg of the active ingredient of thepresent invention.

[1086] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by entericlayer which serves to resist disintegration in the stomach and permitthe inner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

[1087] The novel formulations which are liquid forms may be incorporatedfor administration orally or by injection and include aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, and flavoredemulsions with edible oils such as cottonseed oil, sesame oil, coconutoil, or peanut oil, as well as elixirs and similar pharmaceuticalvehicles.

[1088] Formulations for inhalation or insufflation include solutions andsuspensions in pharmaceutical, aqueous or organic solvents, or mixturesthereof, and powders. The liquid or solid formulations may containsuitable pharmaceutical excipients as described supra. Preferably theformulations are administered by the oral or nasal respiratory route forlocal or systemic effect. Compositions in preferably pharmaceuticalsolvents may be nebulized by use of inert gases. Nebulized solutions maybe breathed directly from the nebulizing device or the nebulizing devicemay be attached to a face mask, tent, or intermittent positive pressurebreathing machine. Solution, suspension, or powder formulations may beadministered, preferably orally or nasally, from devices which deliverthe formulation in an appropriate manner.

[1089] The following formulation examples are illustrative only and arenot intended to limit the scope of the invention in any way. “Activeingredient(s)” means a compound according to formula I or apharmaceutical salt or solvate thereof optionally with one or moreoncolytics.

Formulation Example 1

[1090] Hard gelatin capsules containing the following ingredients areprepared: Quantity Ingredient (mg/capsule) Active ingredient 30.0 Starch305.0 Magnesium stearate 5.0

[1091] The above ingredients are mixed and filled into hard gelatincapsules in 340 mg quantities.

Formulation Example 2

[1092] A tablet formula is prepared using the ingredients below:Quantity Ingredient (mg/tablet) Active ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[1093] The components are blended and compressed to form tablets, eachweighing 240 mg.

Formulation Example 3 A dry powder inhaler formulation is preparedcontaining the following components:

[1094] Ingredient Weight % Active ingredient  5 Lactose 95

[1095] The active ingredient is mixed with the lactose and the mixtureis added to a dry powder inhaling appliance.

Formulation Example 4

[1096] Tablets, each containing 30 mg of active ingredient, are preparedas follows: Quantity Ingredient (mg/tablet) Active ingredient 30.0 mg Starch 45.0 mg  Microcrystalline cellulose 35.0 mg  Polyvinylpyrrolidone4.0 mg (as 10% solution in water) Sodium carboxymethyl starch 4.5 mgMagnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg 

[1097] The active ingredient, starch and cellulose are passed through aNo. 20 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50-60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Formulation Example 5

[1098] Capsules, each containing 40 mg of medicament are made asfollows: Quantity Ingredient (mg/capsule) Active ingredient  40.0 mgStarch 109.0 mg Magnesium stearate  1.0 mg Total 150.0 mg

[1099] The active ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 20 mesh U.S. sieve, and filled intohard gelatin capsules in 150 mg quantities.

Formulation Example 6

[1100] Suppositories, each containing 25 mg of active ingredient aremade as follows: Ingredient Amount Active ingredient   25 mg Saturatedfatty acid glycerides to 2,000 mg

[1101] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7 Suspensions, each containing 50 mg of medicamentper 5.0 ml dose are made as follows:

[1102] Ingredient Amount Active ingredient 50.0 mg Xanthan gum  4.0 mgSodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%)50.0 mg Sucrose 1.75 g   Sodium benzoate 10.0 mg Flavor and Color q.v.Purified water to 5.0 ml

[1103] The active ingredient, sucrose and xanthan gum are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of the microcrystalline cellulose and sodiumcarboxymethyl cellulose in water. The sodium benzoate, flavor, and colorare diluted with some of the water and added with stirring. Sufficientwater is then added to produce the required volume.

Formulation Example 8

[1104] Capsules, each containing 15 mg of medicament, are made asfollows: Quantity Ingredient (mg/capsule) Active ingredient  15.0 mgStarch 407.0 mg Magnesium stearate  3.0 mg Total 425.0 mg

[1105] The active ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 20 mesh U.S. sieve, and filled intohard gelatin capsules in 425 mg quantities.

Formulation Example 9

[1106] An intravenous formulation may be prepared as follows: IngredientQuantity Active ingredient 250.0 mg Isotonic saline  1000 ml

Formulation Example 10

[1107] A topical formulation may be prepared as follows: IngredientQuantity Active ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin20 g White Soft Paraffin to 100 g

[1108] The white soft paraffin is heated until molten. The liquidparaffin and emulsifying wax are incorporated and stirred untildissolved. The active ingredient is added and stirring is continueduntil dispersed. The mixture is then cooled until solid.

Formulation Example 11 Sublingual or buccal tablets, each containing 10mg of active ingredient, may be prepared as follows:

[1109] Quantity Ingredient Per Tablet Active ingredient  10.0 mgGlycerol 210.5 mg Water 143.0 mg Sodium Citrate  4.5 mg PolyvinylAlcohol  26.5 mg Polyvinylpyrrolidone  15.5 mg Total 410.0 mg

[1110] The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50-55° C. and the activeingredient is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 24 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

[1111] Another preferred formulation employed in the methods of thepresent invention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

[1112] Frequently, it will be desirable or necessary to introduce thepharmaceutical formulation to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which isherein incorporated by reference.

[1113] Indirect techniques, which are generally preferred, usuallyinvolve formulating the compositions to provide for drug latentiation bythe conversion of hydrophilic drugs into lipid-soluble drugs orprodrugs. Latentiation is generally achieved through blocking of thehydroxy, carbonyl, sulfate, and primary amine groups present on the drugto render the drug more lipid soluble and amenable to transportationacross the blood-brain barrier. Alternatively, the delivery ofhydrophilic drugs may be enhanced by intra-arterial infusion ofhypertonic solutions, which can transiently open the blood-brainbarrier.

We claim:
 1. A compound of formula I:

where: A is a C₃-C₈ cycloalkyl, optionally substituted 1-3 times with aC₁-C₄ alkyl; het is a five (5) membered heterocyclic ring comprising Nand a second heteroatom selected from N, O, or S; wherein the non-fusedcarbon atom of the heteroaryl ring may be optionally substituted withR^(b): C₁-C₆ alkyl, optionally substituted aryl, optionally substitutedheterocycle, an amino acid ester, CH₂OH, CH₂O-heterocycle, halo, CH₂N₃,CH₂SR¹, CH₂NR⁴R⁶, OR¹, SR¹³, S(CH₂)_(k)-phenyl, or NR⁴R⁶; provided thatwhen het is pyrazole or imidazole, the saturated nitrogen of the hetring may be optionally substituted with R^(a): C₁-C₄ alkyl; k is 0, 1,2, 3, or 4; n is 0, 1, or 2; p is 0 or 1; q is 0, 1, or 2; r is 0, 1, or2; t is 0, 1, 2, 3, or 4; u is 0, 1, 2, 3, or 4; Y is -E-C(O)R³,-E-CH═CHR¹³, -E-C(OH)R¹³, -E-NR⁴R⁵, -E-OR², -E-S(O)_(q)R¹³, -E-SO₂NR⁴R⁶,—C(R¹¹)=NR⁶, or an optionally substituted heterocycle; E is a bond or—C(R¹¹)(R¹¹)—; R¹ is independently at each occurrence hydrogen or C₁-C₆alkyl; R² is independently at each occurrence hydrogen, C₁-C₆ alkyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted aryl, or optionally substitutedheterocycle, C(O)-aryl, or (CH₂)₂NR⁴R⁵; R³ is independently at eachoccurrence hydrogen, C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted heterocycle, OR¹³, or NR⁴R⁶; R⁴is independently at each occurrence hydrogen, C₁-C₆ alkyl, optionallysubstituted (C₁-C₆ alkyl)-aryl, optionally substituted aryl, or R⁴ andR⁵, R⁶, R^(6′) combine to form ═CR¹R¹⁴; R⁵ is independently at eachoccurrence hydrogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, optionally substitutedheterocycle, optionally substituted C₃-Cg cycloalkyl, optionallysubstituted C₆-C₁₀ bicycloalkyl, optionally substituted (C₁-C₄alkyl)-aryl, optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-heterocycle, C(O)C(O)R¹³, C(O)R⁷, CH₂R⁷, SO₂R⁸, a moiety of theformula

or R⁴ and R⁵, together with the nitrogen to which they are attached,combine to form an optionally substituted N-heterocycle; R⁶ isindependently at each occurrence hydrogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,optionally substituted C₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀bicycloalkyl, optionally substituted (C₁-C₄ alkyl)aryl, optionallysubstituted aryl, optionally substituted (C₁-C₄ alkyl)-heterocyc]e,optionally substituted heterocycle, or R⁴ and R⁶, together with thenitrogen to which they are attached, combine to form an optionallysubstituted N-heterocycle; R^(6′) is independently at each occurrencehydrogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, optionally substituted C₃-C₈cycloalkyl, optionally substituted C₆-C₁₀ bicycloalkyl, optionallysubstituted (C₁-C₄ alkyl)-aryl, optionally substituted aryl, optionallysubstituted (C₁-C₄ alkyl)heterocycle, optionally substitutedheterocycle, (C₁-C₄ alkyl)-OR¹³; wherein the (C₁-C₄ alkyl) of the (C₁-C₄alkyl)-OR¹³ may be optionally substituted from 1 to 2 times with C₁-C₄alkyl, optionally substituted aryl, optionally substituted heterocycle;or R⁴ and R^(6′), together with the nitrogen to which they are attached,combine to form an optionally substituted N-heterocycle; R⁷ isindependently at each occurrence optionally substituted C₁-C₆ alkyl,C₁-C₆ alkoxy, (C₁-C₄ alkoxy)-aryl, (C₁-C₄ alkoxy)-heterocycle, (C₁-C₄alkoxy)SiCH₃, optionally substituted (C₃-C₈ cycloalkyl), optionallysubstituted (C₁-C₄ alkyl)-(C₃-Cg cycloalkyl), optionally substituted(C₁-C₄ alkyl)-aryl, optionally substituted aryl, diphenylmethyl,optionally substituted (C₁-C₄ alkyl)-CO-aryl, optionally substitutedCO-aryl, optionally substituted (C₁-C₄ alkyl)-heterocycle, optionallysubstituted CH═CH-heterocycle, optionally substituted phenoxy,optionally substituted heterocycle, optionally substituted (C₁-C₄alkyl)-phenoxy, (CH₂)_(t)S(O)_(t)R¹, (CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵),(CH₂)_(t)C(R¹²)(R⁹)O(R¹⁷), (CH₂)_(t)C(R¹²)(R⁹)S(R¹⁷), or NR⁴R⁶′; R⁸ isindependently at each occurrence optionally substituted C₁-C₆ alkyl,optionally substituted aryl, optionally substituted (C₁-C₄ alkyl)-aryl,optionally substituted (C₁-C₄ alkyl)-heterocycle, or optionallysubstituted heterocycle; R⁹ is independently at each occurrencehydrogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-Cg cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted heterocycle, (CH₂)_(u4)C₁-C₆alkoxy), optionally substituted (CH₂)_(u)—O—(C₃-C₈ cycloalkyl),optionally substituted (CH₂)_(u)—(C₁-C₄ alkoxy)-aryl, optionallysubstituted (CH₂)_(u)—O-aryl, optionally substituted(CH₂)_(u)—O-heterocycle, (C₁-C₄ alkyl)-CO₂—(C₁-C₆ alkyl), optionallysubstituted (C₁-C₄ alkyl)-CO₂—(C₃-C₈ cycloalkyl), optionally substituted(C₁-C₄ alkyl)CO₂—(C₁-C₄ alkyl)-aryl, optionally substituted (C₁-C₄alkyl)-CO₂-aryl, optionally substituted (C₁-C₄ alkyl)-CO₂-heterocycle,or R⁹ and R¹² can combine to form a C₃-C₈ cycloalkyl; R¹⁰ is 0 to 4substituents from the aryl ring independently at each occurrencehydrogen, halo, C(O)R³, cyano, optionally substituted heterocycle,optionally substituted aryl, C≡C—R¹, C₁-C₄ alkoxy, (C₁-C₄ alkyl)-phenyl,NR¹⁹R²⁰, or C₂-C₆ alkenyl; R¹¹ is independently at each occurrencehydrogen, C₁-C₆ alkyl, optionally substituted heterocycle, optionallysubstituted (C₁-C₄ alkyl)heterocycle, optionally substituted aryl, oroptionally substituted (C₁-C₄ alkyl)-aryl; R¹² is independently at eachoccurrence hydrogen, optionally substituted C₁-C₆ alky], optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted (C₁-C₄ alkyl)aryl,optionally substituted aryl, optionally substituted (C₁-C₄alkyl)-heterocycle or optionally substituted heterocycle; R¹³ isindependently at each occurrence hydrogen, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted(C₁-C₄ alkyl)-aryl, Optionally substituted aryl, CO₂CH₂CO₂CH₂CH₃, oroptionally substituted heterocycle; R¹⁴ is independently at eachoccurrence C₁-C₆ alkyl or optionally substituted (C₁-C₄ alkyl)-aryl; R¹⁵is independently at each occurrence hydrogen, C₁-C₆ alkyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₆-C₁₀bicycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted (C₁-C₄ allyl)-heterocycle,optionally substituted heterocycle, C(O)OR¹³, SO₂R⁸, C(O)R¹⁸, or amoiety of the formula

R¹⁶ is independently at each occurrence hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted aryl, optionally substitutedheterocycle, or —COR⁸; or R¹⁶ and R¹⁵, together with the nitrogen towhich they are attached, combine to form an optionally substitutedN-heterocycle; R¹⁷ is independently at each occurrence hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, COR¹⁸, optionally substituted heterocycle, optionallysubstituted (C₁-C₄ alkyl)-heterocycle, optionally substituted C₁-C₆alkoxy, optionally substituted (C₁-C₄ alkoxy)-aryl, optionallysubstituted (C₁-C₄ alkoxy)-heterocycle, (C₁-C₄ alkyl)-N(R¹)(R¹), or anamino acid ester; R¹⁸ is independently at each occurrence hydrogen,optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl, optionally substituted (C₁-C₄ alkyl)-aryl, optionallysubstituted aryl, optionally substituted heterocycle, (C₁-C₄alkyl)-NHCO₂—(C₁-C₄ alkyl), or optionally substituted (C₁-C₄alkyl)-heterocycle; R¹⁹ is independently at each occurrence hydrogen, oroptionally substituted C₁-C₆ alkyl; R²⁰ is independently at eachoccurrence hydrogen, optionally substituted C₁-C₆ alkyl, CH₂₀₁,CO—(C₁-C₄ alkyl); or a pharmaceutical salt thereof.
 2. The compound ofclaim 1 where het is


3. The compound of claim 1 where het is


4. The compound of any one of claims 1-3 where A is 1,3-cyclohexyl. 5.The compound of any one of claims 14 where n is
 0. 6. The compound ofany one of claims 1-5 where o is 0 or
 1. 7. The compound of any one ofclaims 1-6 where Y is E-NR⁴R⁵.
 8. The compound of claim 7 where R⁵ isCOR⁷.
 9. The compound of claim 8 where R⁷ is optionally substitutedheterocycle.
 10. The compound of claim 8 where R⁷ is optionallysubstituted CO-aryl.
 11. The compound of claim 8 where R⁷ is optionallysubstituted CO-heteroaryl.
 12. The compound of claim 8 where R⁷ is.(CH₂) t C(R¹²)(R⁹)N(R¹⁶)(R¹⁵).
 13. The compound of any one of claims1-12 where R^(b) is C₁-C₆ alkyl.
 14. The compound of claim 13 whereR^(b) is methyl.
 15. The compound of any one of claims 1-14 where R¹⁰ ishalo.
 16. The compound of claim 15 where R¹⁰ is chloro.
 17. The compoundof claim 16 where R¹⁰ is 9-chloro.
 18. The compound of claim 17 selectedfrom the group consisting ofN-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-piperidylacetamide,N-[(3S,1R)3(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(2-chloro(4-pyridyloxy))acetamide,N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-imidazolo[5,4-c]quinolin-5-yl))cyclohexyl]methyl}benzamide,N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}benzamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-hydroxy-2-phenylacetamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2(4-fluorophenyl)-2-hydroxyacetamide,N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-3-pyridylcarboxamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide,andN-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamde.19. A method of inhibiting MRP1 in a mammal which comprisesadministering to a mammal in need thereof an effective amount of acompound of formula I, as defined in claim 1, or a pharmaceutical saltthereof.
 20. The method according to claim 19 where the mammal is ahuman.
 21. The method of any one of claims 19-20 where het is


22. The method of any one of claims 19-20 where het is


23. The method of any one of claims 19-22 where A is 1,3-cyclohexyl. 24.The method of any one of claims 19-23 where n is
 0. 25. The method ofany one of claims 19-24 where o is 0 or
 1. 26. The method of any one ofclaims 19-25 where Y is E-NR⁴R⁵.
 27. The method of claim 26 where R⁵ isCOR⁷.
 28. The method of claim 27 where R⁷ is optionally substitutedheterocycle.
 29. The method of claim 27 where R⁷ is optionallysubstituted CO-aryl.
 30. The method of claim 27 where R⁷ is optionallysubstituted CO-heteroaryl.
 31. The method of claim 27 where R⁷ is(CH₂)_(t)C(R¹²)(R⁹)N(R¹⁶)(R¹⁵).
 32. The method of any one of claims19-31 where R^(b) is C₁-C₆ alkyl.
 33. The method of claim 32 where R^(b)is methyl.
 34. The method of any one of claims 19-33 where R¹⁰ is halo.35. The method of claim 34 where R¹⁰ is chloro.
 36. The method of claim35 where R¹⁰ is 9-chloro.
 37. The method of claim 36 selected from thegroup consisting of N-[(3S,1R)3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-piperidylacetamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(2-chloro(4-pyridyloxy))acetamide,N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-imidazolo[5,4-c]quinolin-5-yl))cyclohexyl]methyl}benzamide,N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}benzamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-hydroxy-2-phenylacetamide,N-[(3S,1R)₃-(9-chloro-3-methyl-4-oxo-SH-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-fluorophenyl)-2-hydroxyacetamide,N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-3-pyridylcarboxamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4acetylpiperazinyl)-2-phenylacetamide, andN-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide.38. A method of inhibiting a resistant neoplasm, or a neoplasmsusceptible to resistance, in a mammal which comprises administering toa mammal in need thereof an effective amount of a compound of formula I,as defined in claim 1, or a pharmaceutical salt thereof; in combinationwith an effective amount of one or more oncolytic agents.
 39. The methodaccording to claim 38 where the mammal is a human.
 40. The methodaccording to claim 39 where the oncolytic(s) is selected from:camptosar, melphalan, paclitaxel, vinorelbine, mitoxantrone,doxorubicin, daunorubicin, epirubicin, vincristine, and etopsoside. 41.The method according to claim 39 where the neoplasm is of the Wilm'stype, bladder, bone, breast, lung(small-cell), testis, or thyroid or theneoplasm is associated with acute lymphoblastic and myeloblasticleukemia, neuroblastoma, soft tissue sarcoma, Hodgkin's andnon-Hodgkin's lymphomas, and bronchogenic carcinoma.
 42. The method ofany one of claims 3941 where het is


43. The method of any one of claims 3941 where het is


44. The method of any one of claims 3943 where A is 1,3-cyclohexyl. 45.The method of any one of claims 3944 where n is
 0. 46. The method of anyone of claims 39-45 where o is 0 or
 1. 47. The method of any one ofclaims 3946 where Y is E-NR⁴R⁵.
 48. The method of claim 47 where R⁵ isCOR⁷.
 49. The method of claim 48 where R⁷ is optionally substitutedheterocycle.
 50. The method of claim 48 where R⁷ is optionallysubstituted CO-aryl.
 51. The method of claim 48 where R⁷ is optionallysubstituted CO-heteroaryl.
 52. The method of claim 48 where R⁷ is (CH₂)t C(R¹²)(R⁹)N(R¹⁶)(R¹⁵).
 53. The method of any one of claims 39-52 whereR^(b) is C₁-C₆ alkyl.
 54. The method of claim 53 where R^(b) is methyl.55. The method of any one of claims 39-54 where R¹⁰ is halo.
 56. Themethod of claim 55 where R¹⁰ is chloro.
 57. The method of claim 56 whereR¹⁰ is 9-chloro.
 58. The method of claim 57 selected from the groupconsisting of N-[(3S,1R)-3-(9-chloro-3-methyloxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-piperidylacetamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(2-chloro(4-pyridyloxy))acetamide,N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-imidazolo[5,4-c]quinolin-5-yl))cyclohexyl]methyl}benzamide,N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}benzamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-hydroxy-2-phenylacetamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-fluorophenyl)-2-hydroxyacetamide,N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-3-pyridylcarboxamide,N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide,andN-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide.59. A pharmaceutical formulation comprising a compound of formula I, asdefined in claim 1, or a pharmaceutical salt thereof; in combinationwith one or more pharmaceutical carriers, diluents, or excipientstherefor.
 60. A pharmaceutical formulation comprising: (a) a compound offormula I, as defined in claim 1, or a pharmaceutical salt thereof; (b)one or more oncolytic agents; and (c) one or more pharmaceuticalcarriers, diluents, or excipients therefor.
 61. The formulationaccording to claim 60 where the oncolytic(s) is selected from:camptosar, melphalan, paclitaxel, vinorelbine, mitoxantrone,doxorubicin, daunorubicin, epirubicin, vincristine, and etopsoside. 62.A use of a compound of formula I, as defined in claim 1, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for inhibiting a resistant neoplasm, or a neoplasmsusceptible to resistance in a mammal.
 63. A use of a compound offormula I, as defined in claim 1, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for inhibiting MRP1.
 64. Ause of a compound of formula I, as defined in claim 1, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for inhibiting MRP1 conferred MDR in a resistant neoplasm, ora neoplasm susceptible to resistance in a mammal.
 65. A use of acompound of formula I, as defined in claim 1, in therapy.
 66. Apharmaceutical composition for inhibiting MRP1 in a mammal whichcomprises an effective amount of a compound of formula I, as defined inclaim 1, or a pharmaceutical salt thereof.
 67. The composition accordingto claim 66 where the mammal is a human.
 68. A pharmaceuticalcomposition for inhibiting a resistant neoplasm, or a neoplasmsusceptible to resistance, in a mammal which comprises administering toa mammal in need thereof an effective amount of a compound of formula I,as defined in claim 1, or a pharmaceutical salt thereof; in combinationwith an effective amount of one or more oncolytic agents.
 69. Thecomposition according to claim 68 where the mammal is a human.
 70. Thecomposition according to claim 69 where the oncolytic(s) is selectedfrom: camptosar, melphalan, paclitaxel, vinorelbine, mitoxantrone,doxorubicin, daunorubicin, epirubicin, vincristine, and etopsoside. 71.The composition according to claim 69 where the neoplasm is of theWilm's type, bladder, bone, breast, lung(small-cell), testis, or thyroidor the neoplasm is associated with acute lymphoblastic and myeloblasticleukemia, neuroblastoma, soft tissue sarcoma, Hodgkin's andnon-Hodgkin's lymphomas, and bronchogenic carcinoma.